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Wu L, He J, Shen N, Chen S. Molecular and cellular mechanisms underlying peripheral nerve injury-induced cellular ecological shifts: Implications for neuroregeneration. IBRO Neurosci Rep 2025; 18:120-129. [PMID: 39877591 PMCID: PMC11773043 DOI: 10.1016/j.ibneur.2024.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 12/27/2024] [Indexed: 01/31/2025] Open
Abstract
The peripheral nervous system is a complex ecological network, and its injury triggers a series of fine-grained intercellular regulations that play a crucial role in the repair process. The peripheral nervous system is a sophisticated ecological network, and its injury initiates a cascade of intricate intercellular regulatory processes that are instrumental in the repair process. Despite the advent of sophisticated microsurgical techniques, the repair of peripheral nerve injuries frequently proves inadequate, resulting in adverse effects on patients' quality of life. Accordingly, the continued pursuit of more efficacious treatments is of paramount importance. In this paper, a review of the relevant literature from recent years was conducted to identify the key cell types involved after peripheral nerve injury. These included Schwann cells, macrophages, neutrophils, endothelial cells, and fibroblasts. The review was conducted in depth. This paper analyses the phenotypic changes of these cells after injury, the relevant factors affecting these changes, and how they coordinate with neurons and other cell types. In addition, it explores the potential mechanisms that mediate the behaviour of these cells. Understanding the interactions between these cells and their mutual regulation with neurons is of great significance for the discovery of new neuroregenerative treatments and the identification of potential therapeutic targets.
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Affiliation(s)
- Limao Wu
- School of Clinical Medicine, Hebei University of Engineering, No.81 Congtai Road, Congtai District, Handan City, Hebei Province 056004, China
| | - Jinglan He
- Affiliated Hospital of Hebei University of Engineering, No. 80, Jianshe Street, Fuxing District, Handan City, Hebei Province 056003, China
| | - Na Shen
- Department of Science and Education, Affiliated Hospital of Hebei University of Engineering, No.81 Congtai Road, Congtai District, Handan City, Hebei Province 056004, China
| | - Song Chen
- Orthopaedic Center, Affiliated Hospital of Hebei University of Engineering, No.81 Congtai Road, Congtai District, Handan City, Hebei Province 56004, China
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Khan A, Oliveira J, Lee YS, Guest JD, Silvera R, Pressman Y, Pearse DD, Nettina AE, Goldschmidt-Clermont PJ, Al-Ali H, Williams I, Levi AD, Dietrich WD. Human Schwann Cell-Derived Extracellular Vesicle Isolation, Bioactivity Assessment, and Omics Characterization. Int J Nanomedicine 2025; 20:4123-4144. [PMID: 40201152 PMCID: PMC11977562 DOI: 10.2147/ijn.s500159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 02/05/2025] [Indexed: 04/10/2025] Open
Abstract
Purpose Schwann cell-derived extracellular vesicles (SCEVs) have demonstrated favorable effects in spinal cord, peripheral nerve, and brain injuries. Herein, a scalable, standardized, and efficient isolation methodology of SCEVs obtaining a high yield with a consistent composition as measured by proteomic, lipidomic, and miRNA analysis of their content is described for future clinical use. Methods Human Schwann cells were obtained ethically from nine donors and cultured in a defined growth medium optimized for proliferation. At confluency, the culture was replenished with an isolation medium for 48 hours, then collected and centrifuged sequentially at low and ultra-high speeds to collect purified EVs. The EVs were characterized with mass spectrometry to identify and quantify proteins, lipidomic analysis to assess lipid composition, and next-generation sequencing to confirm miRNA profiles. Each batch of EVs was assessed to ensure their therapeutic potential in promoting neurite outgrowth and cell survival. Results High yields of SCEVs were consistently obtained with similar comprehensive molecular profiles across samples, indicating the reproducibility and reliability of the isolation method. Bioactivity to increase neurite process growth was confirmed in vitro. The predominance of triacylglycerol and phosphatidylcholine suggested its role in cellular membrane dynamics essential for axon regeneration and inflammation mitigation. Of the 2517 identified proteins, 136 were closely related to nervous system repair and regeneration. A total of 732 miRNAs were cataloged, with the top 30 miRNAs potentially contributing to axon growth, neuroprotection, myelination, angiogenesis, the attenuation of neuroinflammation, and key signaling pathways such as VEGFA-VEGFR2 and PI3K-Akt signaling, which are crucial for nervous system repair. Conclusion The study establishes a robust framework for SCEV isolation and their comprehensive characterization, which is consistent with their therapeutic potential in neurological applications. This work provides a valuable proteomic, lipidomic, and miRNA dataset to inform future advancements in applying SCEV to the experimental treatment of neurological injuries and diseases.
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Affiliation(s)
- Aisha Khan
- Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, USA
- The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Julia Oliveira
- The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Yee-Shuan Lee
- Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - James D Guest
- The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA
- Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Risset Silvera
- The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Yelena Pressman
- The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Damien D Pearse
- The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA
- Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Adriana E Nettina
- Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, USA
- The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA
| | | | - Hassan Al-Ali
- The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Indigo Williams
- The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Allan D Levi
- The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA
- Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - W Dalton Dietrich
- The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA
- Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
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Garat J, Di Paolo A, Eastman G, Castillo PE, Sotelo-Silveira J. The Trail of Axonal Protein Synthesis: Origins and Current Functional Landscapes. Neuroscience 2025; 567:195-208. [PMID: 39755230 DOI: 10.1016/j.neuroscience.2024.12.064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 12/03/2024] [Accepted: 12/31/2024] [Indexed: 01/06/2025]
Abstract
Local protein synthesis (LPS) in axons is now recognized as a physiological process, participating both in the maintenance of axonal function and diverse plastic phenomena. In the last decades of the 20th century, the existence and function of axonal LPS were topics of significant debate. Very early, axonal LPS was thought not to occur at all and was later accepted to play roles only during development or in response to specific conditions. However, compelling evidence supports its essential and pervasive role in axonal function in the mature nervous system. Remarkably, in the last five decades, Uruguayan neuroscientists have contributed significantly to demonstrating axonal LPS by studying motor and sensory axons of the peripheral nervous system of mammals, as well as giant axons of the squid and the Mauthner cell of fish. For LPS to occur, a highly regulated transport system must deliver the necessary macromolecules, such as mRNAs and ribosomes. This review discusses key findings related to the localization and abundance of axonal mRNAs and their translation levels, both in basal states and in response to physiological processes, such as learning and memory consolidation, as well as neurodevelopmental and neurodegenerative disorders, including Alzheimer's disease, autism spectrum disorder, and axonal injury. Moreover, we discuss the current understanding of axonal ribosomes, from their localization to the potential roles of locally translated ribosomal proteins, in the context of emerging research that highlights the regulatory roles of the ribosome in translation. Lastly, we address the main challenges and open questions for future studies.
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Affiliation(s)
- Joaquin Garat
- Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable, MEC, Av. Italia 3318, Montevideo, CP 11600, Uruguay
| | - Andres Di Paolo
- Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable, MEC, Av. Italia 3318, Montevideo, CP 11600, Uruguay
| | - Guillermo Eastman
- Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable, MEC, Av. Italia 3318, Montevideo, CP 11600, Uruguay; Department of Biology, University of Virginia, 485 McCormick Rd, Charlottesville, VA, 22904, USA
| | - Pablo E Castillo
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Psychiatry & Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - José Sotelo-Silveira
- Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable, MEC, Av. Italia 3318, Montevideo, CP 11600, Uruguay; Departamento de Biología Celular y Molecular, Facultad de Ciencias, Universidad de la República, Iguá, Montevideo, 4225, CP 11400, Uruguay.
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Yang YM, Ma HB, Xiong Y, Wu Q, Gao XK. PEX11B palmitoylation couples peroxisomal dysfunction with Schwann cells fail in diabetic neuropathy. J Biomed Sci 2025; 32:20. [PMID: 39934809 PMCID: PMC11818136 DOI: 10.1186/s12929-024-01115-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 11/22/2024] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND Diabetic neuropathy (DN) is a prevalent and painful complication of diabetes; however, the mechanisms underlying its pathogenesis remain unclear, and effective clinical treatments are lacking. This study aims to explore the role of peroxisomes in Schwann cells in DN. METHODS The abundance of peroxisomes in the sciatic nerves of mice or Schwann cells was analyzed using laser confocal super-resolution imaging and western blotting. The RFP-GFP-SKL (Ser-Lys-Leu) probe was utilized to assess pexophagy (peroxisomes autophagy) levels. To evaluate the palmitoylation of PEX11B, the acyl-resin assisted capture (acyl-RAC) assay and the Acyl-Biotin Exchange (ABE) assay were employed. Additionally, MR (Mendelian randomization) analysis was conducted to investigate the potential causal relationship between DN and MS (Multiple sclerosis). RESULTS There was a decrease in peroxisomal abundance in the sciatic nerves of diabetic mice, and palmitic acid (PA) induced a reduction in peroxisomal abundance by inhibiting peroxisomal biogenesis in Schwann cells. Mechanistically, PA induced the palmitoylation of PEX11B at C25 site, disrupting its self-interaction and impeding peroxisome elongation. Fenofibrate, a PPARα agonist, effectively rescued peroxisomal dysfunction caused by PA and restored the peroxisomal abundance in diabetic mice. Lastly, MR analysis indicates a notable causal influence of DN on MS, with its onset and progression intricately linked to peroxisomal dysfunction. CONCLUSIONS Targeting the peroxisomal biogenesis pathway may be an effective strategy for preventing and treating DN, underscoring the importance of addressing MS risk at the onset of DN.
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Affiliation(s)
- Yu Mei Yang
- Department of Endocrinology, Center for Metabolism Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Hang Bin Ma
- Department of Radiology, Center of Regenerative and Aging Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Yue Xiong
- Department of Endocrinology, Center for Metabolism Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Qian Wu
- Department of Radiology, Center of Regenerative and Aging Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China.
| | - Xiu Kui Gao
- Department of Endocrinology, Center for Metabolism Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China.
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Guest JD, Santamaria AJ, Solano JP, de Rivero Vaccari JP, Dietrich WD, Pearse DD, Khan A, Levi AD. Challenges in advancing Schwann cell transplantation for spinal cord injury repair. Cytotherapy 2025; 27:36-50. [PMID: 39387736 DOI: 10.1016/j.jcyt.2024.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 08/05/2024] [Accepted: 08/09/2024] [Indexed: 10/15/2024]
Abstract
BACKGROUND AIMS In this article we aimed to provide an expert synthesis of the current status of Schwann cell (SC)therapeutics and potential steps to increase their clinical utility. METHODS We provide an expert synthesis based on preclinical, clinical and manufacturing experience. RESULTS Schwann cells (SCs) are essential for peripheral nerve regeneration and are of interest in supporting axonal repair after spinal cord injury (SCI). SCs can be isolated and cultivated in tissue culture from adult nerve biopsies or generated from precursors and neural progenitors using specific differentiation protocols leading to expanded quantities. In culture, they undergo dedifferentiation to a state similar to "repair" SCs. The known repertoire of SC functions is increasing beyond axon maintenance, myelination, and axonal regeneration to include immunologic regulation and the release of potentially therapeutic extracellular vesicles. Recently, autologous human SC cultures purified under cGMP conditions have been tested in both nerve repair and subacute and chronic SCI clinical trials. Although the effects of SCs to support nerve regeneration are indisputable, their efficacy for clinical SCI has been limited according to the outcomes examined. CONCLUSIONS This review discusses the current limitations of transplanted SCs within the damaged spinal cord environment. Limitations include limited post-transplant cell survival, the inability of SCs to migrate within astrocytic parenchyma, and restricted axonal regeneration out of SC-rich graft regions. We describe steps to amplify the survival and integration of transplanted SCs and to expand the repertoire of uses of SCs, including SC-derived extracellular vesicles. The relative merits of transplanting autologous versus allogeneic SCs and the role that endogenous SCs play in spinal cord repair are described. Finally, we briefly describe the issues requiring solutions to scale up SC manufacturing for commercial use.
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Affiliation(s)
- James D Guest
- The Miami Project to Cure Paralysis and Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.
| | - Andrea J Santamaria
- The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Juan P Solano
- Pediatric Critical Care, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Juan P de Rivero Vaccari
- The Miami Project to Cure Paralysis and Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - William D Dietrich
- The Miami Project to Cure Paralysis and Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Damien D Pearse
- The Miami Project to Cure Paralysis and Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Aisha Khan
- The Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Allan D Levi
- The Miami Project to Cure Paralysis and Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
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6
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Paglione M, Restivo L, Zakhia S, Llobet Rosell A, Terenzio M, Neukomm LJ. Local translatome sustains synaptic function in impaired Wallerian degeneration. EMBO Rep 2025; 26:61-83. [PMID: 39482489 PMCID: PMC11724096 DOI: 10.1038/s44319-024-00301-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 10/07/2024] [Accepted: 10/17/2024] [Indexed: 11/03/2024] Open
Abstract
After injury, severed axons separated from their somas activate programmed axon degeneration, a conserved pathway to initiate their degeneration within a day. Conversely, severed projections deficient in programmed axon degeneration remain morphologically preserved with functional synapses for weeks to months after axotomy. How this synaptic function is sustained remains currently unknown. Here, we show that dNmnat overexpression attenuates programmed axon degeneration in distinct neuronal populations. Severed projections remain morphologically preserved for weeks. When evoked, they elicit a postsynaptic behavior, a readout for preserved synaptic function. We used ribosomal pulldown to isolate the translatome from these projections 1 week after axotomy. Translatome candidates of enriched biological classes identified by transcriptional profiling are validated in a screen using a novel automated system to detect evoked antennal grooming as a proxy for preserved synaptic function. RNAi-mediated knockdown reveals that transcripts of the mTORC1 pathway, a mediator of protein synthesis, and of candidate genes involved in protein ubiquitination and Ca2+ homeostasis are required for preserved synaptic function. Our translatome dataset also uncovers several uncharacterized Drosophila genes associated with human disease. It may offer insights into novel avenues for therapeutic treatments.
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Affiliation(s)
- Maria Paglione
- Department of Fundamental Neurosciences, University of Lausanne, 1005, Lausanne, Switzerland
- Lemanic Neuroscience Doctoral School (LNDS), Lausanne, Switzerland
| | - Leonardo Restivo
- Department of Fundamental Neurosciences, University of Lausanne, 1005, Lausanne, Switzerland
| | - Sarah Zakhia
- Molecular Neuroscience Unit, Okinawa Institute of Science and Technology Graduate University, Kunigami-gun, Okinawa, 904-0412, Japan
| | - Arnau Llobet Rosell
- Department of Fundamental Neurosciences, University of Lausanne, 1005, Lausanne, Switzerland
| | - Marco Terenzio
- Molecular Neuroscience Unit, Okinawa Institute of Science and Technology Graduate University, Kunigami-gun, Okinawa, 904-0412, Japan
| | - Lukas J Neukomm
- Department of Fundamental Neurosciences, University of Lausanne, 1005, Lausanne, Switzerland.
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7
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Najdaghi S, Davani DN, Fouladseresht H, Ebrahimi N, Sullman MJM, Moradi M, Eskandari N. The Role of Extracellular Vesicles and Microparticles in Central Nervous System Disorders: Mechanisms, Biomarkers, and Therapeutic Potential. Cell Mol Neurobiol 2024; 44:82. [PMID: 39625540 PMCID: PMC11614997 DOI: 10.1007/s10571-024-01518-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Accepted: 11/15/2024] [Indexed: 12/06/2024]
Abstract
Microscopic, membranous vesicles known as extracellular vesicles (EVs) have been proposed to play a role in the mechanisms underlying central nervous system (CNS) diseases. EVs are secreted by a variety of cells, including myeloid, endothelial, microglial, oligodendroglial, and mesenchymal stem cells (MSCs). Body fluids such as plasma, urine, and cerebrospinal fluid (CSF) contain microparticles (MPs). The detection of MPs in CSF may indicate genetic or environmental susceptibility to conditions such as schizophrenia, schizoaffective disorder, and bipolar disorder. MPs of different origins can exhibit changes in specific biomarkers at various stages of the disease, aiding in the diagnosis and monitoring of neurological conditions. However, understanding the role and clinical applications of MPs is complicated by challenges such as their isolation and dual roles within the CNS. In this review, we discuss the history, characteristics, and roles of MPs in CNS diseases. We also provide practical insights for future research and highlight the challenges that obscure the therapeutic potential of MPs.
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Affiliation(s)
- Soroush Najdaghi
- Neuroscience Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Hamed Fouladseresht
- Immunology Department, Medical School, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Narges Ebrahimi
- Neuroscience Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
- Immunology Department, Medical School, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mark J M Sullman
- Department of Social Sciences, School of Humanities and Social Sciences, University of Nicosia, Nicosia, Cyprus
- Department of Life and Health Sciences, School of Humanities and Social Sciences, University of Nicosia, Nicosia, Cyprus
| | - Marjan Moradi
- Departement of Genetics, School of Science, Shahrekord University, Shahrakord, Iran
| | - Nahid Eskandari
- Immunology Department, Medical School, Isfahan University of Medical Sciences, Isfahan, Iran.
- Applied Physiology Research Center, Cardiovascular Research Institute, Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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8
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Tomé D, Almeida RD. The injured axon: intrinsic mechanisms driving axonal regeneration. Trends Neurosci 2024; 47:875-891. [PMID: 39438216 DOI: 10.1016/j.tins.2024.09.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 09/10/2024] [Accepted: 09/26/2024] [Indexed: 10/25/2024]
Abstract
Injury to the central nervous system (CNS) often results in permanent neurological impairments because axons fail to regenerate and re-establish lost synaptic contacts. By contrast, peripheral neurons can activate a pro-regenerative program and regenerate following a nerve lesion. This relies on an intricate intracellular communication system between the severed axon and the cell body. Locally activated signaling molecules are retrogradely transported to the soma to promote the epigenetic and transcriptional changes required for the injured neuron to regain growth competence. These signaling events rely heavily on intra-axonal translation and mitochondrial trafficking into the severed axon. Here, we discuss the interplay between these mechanisms and the main intrinsic barriers to axonal regeneration. We also examine the potential of manipulating these processes for driving CNS repair.
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Affiliation(s)
- Diogo Tomé
- iBiMED- Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, Aveiro, Portugal; CNC, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
| | - Ramiro D Almeida
- iBiMED- Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, Aveiro, Portugal; CNC, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
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9
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Abd Razak NH, Idris J, Hassan NH, Zaini F, Muhamad N, Daud MF. Unveiling the Role of Schwann Cell Plasticity in the Pathogenesis of Diabetic Peripheral Neuropathy. Int J Mol Sci 2024; 25:10785. [PMID: 39409114 PMCID: PMC11476695 DOI: 10.3390/ijms251910785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 08/23/2024] [Accepted: 08/24/2024] [Indexed: 10/20/2024] Open
Abstract
Diabetic peripheral neuropathy (DPN) is a prevalent complication of diabetes that affects a significant proportion of diabetic patients worldwide. Although the pathogenesis of DPN involves axonal atrophy and demyelination, the exact mechanisms remain elusive. Current research has predominantly focused on neuronal damage, overlooking the potential contributions of Schwann cells, which are the predominant glial cells in the peripheral nervous system. Schwann cells play a critical role in neurodevelopment, neurophysiology, and nerve regeneration. This review highlights the emerging understanding of the involvement of Schwann cells in DPN pathogenesis. This review explores the potential role of Schwann cell plasticity as an underlying cellular and molecular mechanism in the development of DPN. Understanding the interplay between Schwann cell plasticity and diabetes could reveal novel strategies for the treatment and management of DPN.
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Affiliation(s)
- Nurul Husna Abd Razak
- Institute of Medical Science Technology, Universiti Kuala Lumpur (UniKL), A1-1, Jalan TKS 1, Taman Kajang Sentral, Kajang 43000, Selangor, Malaysia; (N.H.A.R.); (J.I.); (N.H.H.)
| | - Jalilah Idris
- Institute of Medical Science Technology, Universiti Kuala Lumpur (UniKL), A1-1, Jalan TKS 1, Taman Kajang Sentral, Kajang 43000, Selangor, Malaysia; (N.H.A.R.); (J.I.); (N.H.H.)
| | - Nur Hidayah Hassan
- Institute of Medical Science Technology, Universiti Kuala Lumpur (UniKL), A1-1, Jalan TKS 1, Taman Kajang Sentral, Kajang 43000, Selangor, Malaysia; (N.H.A.R.); (J.I.); (N.H.H.)
| | - Fazlin Zaini
- Royal College of Medicine Perak, Universiti Kuala Lumpur (UniKL), No. 3, Jalan Greentown, Ipoh 30450, Perak, Malaysia; (F.Z.); (N.M.)
| | - Noorzaid Muhamad
- Royal College of Medicine Perak, Universiti Kuala Lumpur (UniKL), No. 3, Jalan Greentown, Ipoh 30450, Perak, Malaysia; (F.Z.); (N.M.)
| | - Muhammad Fauzi Daud
- Institute of Medical Science Technology, Universiti Kuala Lumpur (UniKL), A1-1, Jalan TKS 1, Taman Kajang Sentral, Kajang 43000, Selangor, Malaysia; (N.H.A.R.); (J.I.); (N.H.H.)
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Hushmandi K, Einollahi B, Aow R, Suhairi SB, Klionsky DJ, Aref AR, Reiter RJ, Makvandi P, Rabiee N, Xu Y, Nabavi N, Saadat SH, Farahani N, Kumar AP. Investigating the interplay between mitophagy and diabetic neuropathy: Uncovering the hidden secrets of the disease pathology. Pharmacol Res 2024; 208:107394. [PMID: 39233055 PMCID: PMC11934918 DOI: 10.1016/j.phrs.2024.107394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 08/18/2024] [Accepted: 08/30/2024] [Indexed: 09/06/2024]
Abstract
Mitophagy, the cellular process of selectively eliminating damaged mitochondria, plays a crucial role in maintaining metabolic balance and preventing insulin resistance, both key factors in type 2 diabetes mellitus (T2DM) development. When mitophagy malfunctions in diabetic neuropathy, it triggers a cascade of metabolic disruptions, including reduced energy production, increased oxidative stress, and cell death, ultimately leading to various complications. Thus, targeting mitophagy to enhance the process may have emerged as a promising therapeutic strategy for T2DM and its complications. Notably, plant-derived compounds with β-cell protective and mitophagy-stimulating properties offer potential as novel therapeutic agents. This review highlights the intricate mechanisms linking mitophagy dysfunction to T2DM and its complications, particularly neuropathy, elucidating potential therapeutic interventions for this debilitating disease.
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Affiliation(s)
- Kiavash Hushmandi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Behzad Einollahi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Rachel Aow
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Suhana Binte Suhairi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Daniel J Klionsky
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Amir Reza Aref
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, Long School of Medicine, San Antonio, TX, USA
| | - Pooyan Makvandi
- Department of Biomaterials, Saveetha Dental College and Hospitals, SIMATS, Saveetha University, Chennai 600077, India; University Centre for Research & Development, Chandigarh University, Mohali, Punjab 140413, India
| | - Navid Rabiee
- Department of Biomaterials, Saveetha Dental College and Hospitals, SIMATS, Saveetha University, Chennai 600077, India
| | - Yi Xu
- Department of Science & Technology, Department of Urology, NanoBioMed Group, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou 324000, China
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia V8V 1P7, Canada
| | - Seyed Hassan Saadat
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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11
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Frostadottir D, Welinder C, Perez R, Dahlin LB. Quantitative mass spectrometry analysis of the injured proximal and distal human digital nerve ends. Front Mol Neurosci 2024; 17:1425780. [PMID: 39015129 PMCID: PMC11250671 DOI: 10.3389/fnmol.2024.1425780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 06/17/2024] [Indexed: 07/18/2024] Open
Abstract
Introduction Proteomic analysis of injured human peripheral nerves, particularly focusing on events occurring in the proximal and distal nerve ends, remains relatively underexplored. This study aimed to investigate the molecular patterns underlying a digital nerve injury, focusing on differences in protein expression between the proximal and distal nerve ends. Methods A total of 26 human injured digital nerve samples (24 men; 2 women; median age 47 [30-66] years), harvested during primary nerve repair within 48 h post-injury from proximal and distal nerve ends, were analyzed using mass spectrometry. Results A total of 3,914 proteins were identified, with 127 proteins showing significant differences in abundance between the proximal and the distal nerve ends. The downregulation of proteins in the distal nerve end was associated with synaptic transmission, autophagy, neurotransmitter regulation, cell adhesion and migration. Conversely, proteins upregulated in the distal nerve end were implicated in cellular stress response, neuromuscular junction stability and muscle contraction, neuronal excitability and neurotransmitter release, synaptic vesicle recycling and axon guidance and angiogenesis. Discussion Investigation of proteins, with functional annotations analysis, in proximal and the distal ends of human injured digital nerves, revealed dynamic cellular responses aimed at promoting tissue degeneration and restoration, while suppressing non-essential processes.
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Affiliation(s)
- Drifa Frostadottir
- Department of Translational Medicine – Hand Surgery, Lund University, Malmö, Sweden
- Department of Hand Surgery, Skåne University Hospital, Malmö, Sweden
| | - Charlotte Welinder
- Faculty of Medicine, Department of Clinical Sciences, Mass Spectrometry, Lund University, Lund, Sweden
| | - Raquel Perez
- Department of Translational Medicine – Hand Surgery, Lund University, Malmö, Sweden
- Unit for Social Epidemiology, Department of Clinical Sciences, Malmö, Lund University, Malmö, Sweden
| | - Lars B. Dahlin
- Department of Translational Medicine – Hand Surgery, Lund University, Malmö, Sweden
- Department of Hand Surgery, Skåne University Hospital, Malmö, Sweden
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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12
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Shender VO, Anufrieva KS, Shnaider PV, Arapidi GP, Pavlyukov MS, Ivanova OM, Malyants IK, Stepanov GA, Zhuravlev E, Ziganshin RH, Butenko IO, Bukato ON, Klimina KM, Veselovsky VA, Grigorieva TV, Malanin SY, Aleshikova OI, Slonov AV, Babaeva NA, Ashrafyan LA, Khomyakova E, Evtushenko EG, Lukina MM, Wang Z, Silantiev AS, Nushtaeva AA, Kharlampieva DD, Lazarev VN, Lashkin AI, Arzumanyan LK, Petrushanko IY, Makarov AA, Lebedeva OS, Bogomazova AN, Lagarkova MA, Govorun VM. Therapy-induced secretion of spliceosomal components mediates pro-survival crosstalk between ovarian cancer cells. Nat Commun 2024; 15:5237. [PMID: 38898005 PMCID: PMC11187153 DOI: 10.1038/s41467-024-49512-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 06/07/2024] [Indexed: 06/21/2024] Open
Abstract
Ovarian cancer often develops resistance to conventional therapies, hampering their effectiveness. Here, using ex vivo paired ovarian cancer ascites obtained before and after chemotherapy and in vitro therapy-induced secretomes, we show that molecules secreted by ovarian cancer cells upon therapy promote cisplatin resistance and enhance DNA damage repair in recipient cancer cells. Even a short-term incubation of chemonaive ovarian cancer cells with therapy-induced secretomes induces changes resembling those that are observed in chemoresistant patient-derived tumor cells after long-term therapy. Using integrative omics techniques, we find that both ex vivo and in vitro therapy-induced secretomes are enriched with spliceosomal components, which relocalize from the nucleus to the cytoplasm and subsequently into the extracellular vesicles upon treatment. We demonstrate that these molecules substantially contribute to the phenotypic effects of therapy-induced secretomes. Thus, SNU13 and SYNCRIP spliceosomal proteins promote therapy resistance, while the exogenous U12 and U6atac snRNAs stimulate tumor growth. These findings demonstrate the significance of spliceosomal network perturbation during therapy and further highlight that extracellular signaling might be a key factor contributing to the emergence of ovarian cancer therapy resistance.
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Affiliation(s)
- Victoria O Shender
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, 119435, Russian Federation.
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow, 119435, Russian Federation.
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, 117997, Russian Federation.
| | - Ksenia S Anufrieva
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, 119435, Russian Federation
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow, 119435, Russian Federation
| | - Polina V Shnaider
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, 119435, Russian Federation
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow, 119435, Russian Federation
- Faculty of Biology; Lomonosov Moscow State University, Moscow, 119991, Russian Federation
| | - Georgij P Arapidi
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, 119435, Russian Federation
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow, 119435, Russian Federation
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, 117997, Russian Federation
- Moscow Institute of Physics and Technology (State University), Dolgoprudny, 141701, Russian Federation
| | - Marat S Pavlyukov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, 117997, Russian Federation
| | - Olga M Ivanova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, 119435, Russian Federation
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow, 119435, Russian Federation
| | - Irina K Malyants
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow, 119435, Russian Federation
- Faculty of Chemical-Pharmaceutical Technologies and Biomedical Drugs, Mendeleev University of Chemical Technology of Russia, Moscow, 125047, Russian Federation
| | - Grigory A Stepanov
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Novosibirsk, 630090, Russian Federation
- Department of Natural Sciences, Novosibirsk State University, Novosibirsk, 630090, Russia
| | - Evgenii Zhuravlev
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Novosibirsk, 630090, Russian Federation
| | - Rustam H Ziganshin
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, 117997, Russian Federation
| | - Ivan O Butenko
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow, 119435, Russian Federation
| | - Olga N Bukato
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow, 119435, Russian Federation
| | - Ksenia M Klimina
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, 119435, Russian Federation
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow, 119435, Russian Federation
| | - Vladimir A Veselovsky
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow, 119435, Russian Federation
| | | | | | - Olga I Aleshikova
- National Medical Scientific Centre of Obstetrics, Gynaecology and Perinatal Medicine named after V.I. Kulakov, Moscow, 117198, Russian Federation
- Russian Research Center of Roentgenology and Radiology, Moscow, 117997, Russian Federation
| | - Andrey V Slonov
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow, 119435, Russian Federation
| | - Nataliya A Babaeva
- National Medical Scientific Centre of Obstetrics, Gynaecology and Perinatal Medicine named after V.I. Kulakov, Moscow, 117198, Russian Federation
- Russian Research Center of Roentgenology and Radiology, Moscow, 117997, Russian Federation
| | - Lev A Ashrafyan
- National Medical Scientific Centre of Obstetrics, Gynaecology and Perinatal Medicine named after V.I. Kulakov, Moscow, 117198, Russian Federation
- Russian Research Center of Roentgenology and Radiology, Moscow, 117997, Russian Federation
| | | | - Evgeniy G Evtushenko
- Faculty of Chemistry; Lomonosov Moscow State University, Moscow, 119991, Russian Federation
| | - Maria M Lukina
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, 119435, Russian Federation
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow, 119435, Russian Federation
| | - Zixiang Wang
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University; Jinan, 250012, Shandong, China
| | - Artemiy S Silantiev
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow, 119435, Russian Federation
| | - Anna A Nushtaeva
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Novosibirsk, 630090, Russian Federation
| | - Daria D Kharlampieva
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow, 119435, Russian Federation
| | - Vassili N Lazarev
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, 119435, Russian Federation
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow, 119435, Russian Federation
| | - Arseniy I Lashkin
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow, 119435, Russian Federation
| | - Lorine K Arzumanyan
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow, 119435, Russian Federation
| | - Irina Yu Petrushanko
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russian Federation
| | - Alexander A Makarov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russian Federation
| | - Olga S Lebedeva
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, 119435, Russian Federation
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow, 119435, Russian Federation
| | - Alexandra N Bogomazova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, 119435, Russian Federation
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow, 119435, Russian Federation
| | - Maria A Lagarkova
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow, 119435, Russian Federation
| | - Vadim M Govorun
- Research Institute for Systems Biology and Medicine, Moscow, 117246, Russian Federation
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Zhang Y, Xu T, Xie J, Wu H, Hu W, Yuan X. MSC-derived mitochondria promote axonal regeneration via Atf3 gene up-regulation by ROS induced DNA double strand breaks at transcription initiation region. Cell Commun Signal 2024; 22:240. [PMID: 38664711 PMCID: PMC11046838 DOI: 10.1186/s12964-024-01617-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 04/16/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND The repair of peripheral nerve injury poses a clinical challenge, necessitating further investigation into novel therapeutic approaches. In recent years, bone marrow mesenchymal stromal cell (MSC)-derived mitochondrial transfer has emerged as a promising therapy for cellular injury, with reported applications in central nerve injury. However, its potential therapeutic effect on peripheral nerve injury remains unclear. METHODS We established a mouse sciatic nerve crush injury model. Mitochondria extracted from MSCs were intraneurally injected into the injured sciatic nerves. Axonal regeneration was observed through whole-mount nerve imaging. The dorsal root ganglions (DRGs) corresponding to the injured nerve were harvested to test the gene expression, reactive oxygen species (ROS) levels, as well as the degree and location of DNA double strand breaks (DSBs). RESULTS The in vivo experiments showed that the mitochondrial injection therapy effectively promoted axon regeneration in injured sciatic nerves. Four days after injection of fluorescently labeled mitochondria into the injured nerves, fluorescently labeled mitochondria were detected in the corresponding DRGs. RNA-seq and qPCR results showed that the mitochondrial injection therapy enhanced the expression of Atf3 and other regeneration-associated genes in DRG neurons. Knocking down of Atf3 in DRGs by siRNA could diminish the therapeutic effect of mitochondrial injection. Subsequent experiments showed that mitochondrial injection therapy could increase the levels of ROS and DSBs in injury-associated DRG neurons, with this increase being correlated with Atf3 expression. ChIP and Co-IP experiments revealed an elevation of DSB levels within the transcription initiation region of the Atf3 gene following mitochondrial injection therapy, while also demonstrating a spatial proximity between mitochondria-induced DSBs and CTCF binding sites. CONCLUSION These findings suggest that MSC-derived mitochondria injected into the injured nerves can be retrogradely transferred to DRG neuron somas via axoplasmic transport, and increase the DSBs at the transcription initiation regions of the Atf3 gene through ROS accumulation, which rapidly release the CTCF-mediated topological constraints on chromatin interactions. This process may enhance spatial interactions between the Atf3 promoter and enhancer, ultimately promoting Atf3 expression. The up-regulation of Atf3 induced by mitochondria further promotes the expression of downstream regeneration-associated genes and facilitates axon regeneration.
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Affiliation(s)
- Yingchi Zhang
- Department of Traumatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, Hubei, 430030, People's Republic of China
| | - Tao Xu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, Hubei, 430030, People's Republic of China
| | - Jie Xie
- Department of Traumatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, Hubei, 430030, People's Republic of China
| | - Hua Wu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, Hubei, 430030, People's Republic of China
| | - Weihua Hu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, Hubei, 430030, People's Republic of China.
| | - Xuefeng Yuan
- Department of Traumatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, Hubei, 430030, People's Republic of China.
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14
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Seedhom MO, Dersh D, Holly J, Pavon-Eternod M, Wei J, Angel M, Shores L, David A, Santos J, Hickman H, Yewdell JW. Paradoxical imbalance between activated lymphocyte protein synthesis capacity and rapid division rate. eLife 2024; 12:RP89015. [PMID: 38512721 PMCID: PMC10957176 DOI: 10.7554/elife.89015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2024] Open
Abstract
Rapid lymphocyte cell division places enormous demands on the protein synthesis machinery. Flow cytometric measurement of puromycylated ribosome-associated nascent chains after treating cells or mice with translation initiation inhibitors reveals that ribosomes in resting lymphocytes in vitro and in vivo elongate at typical rates for mammalian cells. Intriguingly, elongation rates can be increased up to 30% by activation in vivo or fever temperature in vitro. Resting and activated lymphocytes possess abundant monosome populations, most of which actively translate in vivo, while in vitro, nearly all can be stalled prior to activation. Quantitating lymphocyte protein mass and ribosome count reveals a paradoxically high ratio of cellular protein to ribosomes insufficient to support their rapid in vivo division, suggesting that the activated lymphocyte proteome in vivo may be generated in an unusual manner. Our findings demonstrate the importance of a global understanding of protein synthesis in lymphocytes and other rapidly dividing immune cells.
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Affiliation(s)
- Mina O Seedhom
- National Institute of Allergy and Infectious DiseasesBethesdaUnited States
| | - Devin Dersh
- National Institute of Allergy and Infectious DiseasesBethesdaUnited States
| | - Jaroslav Holly
- National Institute of Allergy and Infectious DiseasesBethesdaUnited States
| | | | - Jiajie Wei
- National Institute of Allergy and Infectious DiseasesBethesdaUnited States
| | - Matthew Angel
- National Institute of Allergy and Infectious DiseasesBethesdaUnited States
| | - Lucas Shores
- National Institute of Allergy and Infectious DiseasesBethesdaUnited States
| | - Alexandre David
- CNRS UMR-5203; INSERM U661; UM1; UM2, Institut de Génomique FonctionnelleMontpellierFrance
| | - Jefferson Santos
- National Institute of Allergy and Infectious DiseasesBethesdaUnited States
| | - Heather Hickman
- National Institute of Allergy and Infectious DiseasesBethesdaUnited States
| | - Jonathan W Yewdell
- National Institute of Allergy and Infectious DiseasesBethesdaUnited States
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15
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Di Liegro CM, Schiera G, Schirò G, Di Liegro I. Role of Post-Transcriptional Regulation in Learning and Memory in Mammals. Genes (Basel) 2024; 15:337. [PMID: 38540396 PMCID: PMC10970538 DOI: 10.3390/genes15030337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 02/27/2024] [Accepted: 03/01/2024] [Indexed: 06/14/2024] Open
Abstract
After many decades, during which most molecular studies on the regulation of gene expression focused on transcriptional events, it was realized that post-transcriptional control was equally important in order to determine where and when specific proteins were to be synthesized. Translational regulation is of the most importance in the brain, where all the steps of mRNA maturation, transport to different regions of the cells and actual expression, in response to specific signals, constitute the molecular basis for neuronal plasticity and, as a consequence, for structural stabilization/modification of synapses; notably, these latter events are fundamental for the highest brain functions, such as learning and memory, and are characterized by long-term potentiation (LTP) of specific synapses. Here, we will discuss the molecular bases of these fundamental events by considering both the role of RNA-binding proteins (RBPs) and the effects of non-coding RNAs involved in controlling splicing, editing, stability and translation of mRNAs. Importantly, it has also been found that dysregulation of mRNA metabolism/localization is involved in many pathological conditions, arising either during brain development or in the adult nervous system.
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Affiliation(s)
- Carlo Maria Di Liegro
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90128 Palermo, Italy; (C.M.D.L.); (G.S.)
| | - Gabriella Schiera
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90128 Palermo, Italy; (C.M.D.L.); (G.S.)
| | - Giuseppe Schirò
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy;
- Neurology and Multiple Sclerosis Center, Unità Operativa Complessa (UOC), Foundation Institute “G. Giglio”, 90015 Cefalù, Italy
| | - Italia Di Liegro
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy;
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16
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Civelek E, Kabatas S, Savrunlu EC, Diren F, Kaplan N, Ofluoğlu D, Karaöz E. Effects of exosomes from mesenchymal stem cells on functional recovery of a patient with total radial nerve injury: A pilot study. World J Stem Cells 2024; 16:19-32. [PMID: 38292440 PMCID: PMC10824039 DOI: 10.4252/wjsc.v16.i1.19] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 11/30/2023] [Accepted: 01/05/2024] [Indexed: 01/22/2024] Open
Abstract
BACKGROUND Peripheral nerve injury can result in significant clinical complications that have uncertain prognoses. Currently, there is a lack of effective pharmacological interventions for nerve damage, despite the existence of several small compounds, peptides, hormones, and growth factors that have been suggested as potential enhancers of neuron regeneration. Despite the objective of achieving full functional restoration by surgical intervention, the persistent challenge of inadequate functional recovery remains a significant concern in the context of peripheral nerve injuries. AIM To examine the impact of exosomes on the process of functional recovery following a complete radial nerve damage. METHODS A male individual, aged 24, who is right-hand dominant and an immigrant, arrived with an injury caused by a knife assault. The cut is located on the left arm, specifically below the elbow. The neurological examination and electrodiagnostic testing reveal evidence of left radial nerve damage. The sural autograft was utilized for repair, followed by the application of 1 mL of mesenchymal stem cell-derived exosome, comprising 5 billion microvesicles. This exosome was split into four equal volumes of 0.25 mL each and delivered microsurgically to both the proximal and distal stumps using the subepineural pathway. The patient was subjected to a period of 180 d during which they had neurological examination and electrodiagnostic testing. RESULTS The duration of the patient's follow-up period was 180 d. An increasing Tinel's sign and sensory-motor recovery were detected even at the 10th wk following nerve grafting. Upon the conclusion of the 6-mo post-treatment period, an evaluation was conducted to measure the extent of improvement in motor and sensory functions of the nerve. This assessment was based on the British Medical Research Council scale and the Mackinnon-Dellon scale. The results indicated that the level of improvement in motor function was classified as M5, denoting an excellent outcome. Additionally, the level of improvement in sensory function was classified as S3+, indicating a good outcome. It is noteworthy that these assessments were conducted in the absence of physical therapy. At the 10th wk post-injury, despite the persistence of substantial axonal damage, the nerve exhibited indications of nerve re-innervation as evidenced by control electromyography (EMG). In contrast to the preceding. EMG analysis revealed a significant electrophysiological enhancement in the EMG conducted at the 6th-mo follow-up, indicating ongoing regeneration. CONCLUSION Enhanced comprehension of the neurobiological ramifications associated with peripheral nerve damage, as well as the experimental and therapy approaches delineated in this investigation, holds the potential to catalyze future clinical progress.
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Affiliation(s)
- Erdinç Civelek
- Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, Gaziosmanpaşa 34255, Istanbul, Turkey.
| | - Serdar Kabatas
- Department of Neurosurgery, University of Health Sciences Turkey, Gaziosmanpaşa Training and Research Hospital, Gaziosmanpaşa 34255, Istanbul, Turkey
- Center for Stem Cell & Gene Therapy Research and Practice, University of Health Sciences Turkey, Gaziosmanpaşa 34255, Istanbul, Turkey
| | - Eyüp Can Savrunlu
- Department of Neurosurgery, Nevşehir State Hospital, Nevşehir 50300, Turkey
| | - Furkan Diren
- Department of Neurosurgery, University of Health Sciences Turkey, Gaziosmanpaşa Training and Research Hospital, Gaziosmanpaşa 34255, Istanbul, Turkey
| | - Necati Kaplan
- Department of Neurosurgery, Istanbul Rumeli University, Çorlu Reyap Hospital, Çorlu 59860, Tekirdağ, Turkey
| | - Demet Ofluoğlu
- Department of Physical Medicine and Rehabilitation, Ofluoğlu Klinik, Göztepe 34728, Istanbul, Turkey
| | - Erdal Karaöz
- Liv Hospital, Center for Regenerative Medicine and Stem Cell Research & Manufacturing (LivMedCell), Beşiktaş 34340, Istanbul, Turkey
- Department of Histology and Embryology, Istinye University, Faculty of Medicine, Zeytinburnu 34010, Istanbul, Turkey
- Istinye University, Center for Stem Cell and Tissue Engineering Research and Practice, Beşiktaş 34340, Istanbul, Turkey
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17
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Schiera G, Di Liegro CM, Schirò G, Sorbello G, Di Liegro I. Involvement of Astrocytes in the Formation, Maintenance, and Function of the Blood-Brain Barrier. Cells 2024; 13:150. [PMID: 38247841 PMCID: PMC10813980 DOI: 10.3390/cells13020150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/08/2024] [Accepted: 01/11/2024] [Indexed: 01/23/2024] Open
Abstract
The blood-brain barrier (BBB) is a fundamental structure that protects the composition of the brain by determining which ions, metabolites, and nutrients are allowed to enter the brain from the blood or to leave it towards the circulation. The BBB is structurally composed of a layer of brain capillary endothelial cells (BCECs) bound to each other through tight junctions (TJs). However, its development as well as maintenance and properties are controlled by the other brain cells that contact the BCECs: pericytes, glial cells, and even neurons themselves. Astrocytes seem, in particular, to have a very important role in determining and controlling most properties of the BBB. Here, we will focus on these latter cells, since the comprehension of their roles in brain physiology has been continuously expanding, even including the ability to participate in neurotransmission and in complex functions such as learning and memory. Accordingly, pathological conditions that alter astrocytic functions can alter the BBB's integrity, thus compromising many brain activities. In this review, we will also refer to different kinds of in vitro BBB models used to study the BBB's properties, evidencing its modifications under pathological conditions.
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Affiliation(s)
- Gabriella Schiera
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (Dipartimento di Scienzee Tecnologie Biologiche, Chimiche e Farmaceutiche) (STEBICEF), University of Palermo, 90128 Palermo, Italy; (G.S.); (C.M.D.L.)
| | - Carlo Maria Di Liegro
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (Dipartimento di Scienzee Tecnologie Biologiche, Chimiche e Farmaceutiche) (STEBICEF), University of Palermo, 90128 Palermo, Italy; (G.S.); (C.M.D.L.)
| | - Giuseppe Schirò
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (G.S.); (G.S.)
- Neurology and Multiple Sclerosis Center, Unità Operativa Complessa (UOC), Foundation Institute “G. Giglio”, 90015 Cefalù, Italy
| | - Gabriele Sorbello
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (G.S.); (G.S.)
| | - Italia Di Liegro
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (G.S.); (G.S.)
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Krishnan A, Verge VMK, Zochodne DW. Hallmarks of peripheral nerve injury and regeneration. HANDBOOK OF CLINICAL NEUROLOGY 2024; 201:1-17. [PMID: 38697733 DOI: 10.1016/b978-0-323-90108-6.00014-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2024]
Abstract
Peripheral nerves are functional networks in the body. Disruption of these networks induces varied functional consequences depending on the types of nerves and organs affected. Despite the advances in microsurgical repair and understanding of nerve regeneration biology, restoring full functions after severe traumatic nerve injuries is still far from achieved. While a blunted growth response from axons and errors in axon guidance due to physical barriers may surface as the major hurdles in repairing nerves, critical additional cellular and molecular aspects challenge the orderly healing of injured nerves. Understanding the systematic reprogramming of injured nerves at the cellular and molecular levels, referred to here as "hallmarks of nerve injury regeneration," will offer better ideas. This chapter discusses the hallmarks of nerve injury and regeneration and critical points of failures in the natural healing process. Potential pharmacological and nonpharmacological intervention points for repairing nerves are also discussed.
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Affiliation(s)
- Anand Krishnan
- Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada; Cameco MS Neuroscience Research Centre (CMSNRC), Saskatoon, SK, Canada.
| | - Valerie M K Verge
- Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada; Cameco MS Neuroscience Research Centre (CMSNRC), Saskatoon, SK, Canada.
| | - Douglas W Zochodne
- Neuroscience and Mental Health Institute and Division of Neurology, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
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19
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Alexandris AS, Koliatsos VE. NAD +, Axonal Maintenance, and Neurological Disease. Antioxid Redox Signal 2023; 39:1167-1184. [PMID: 37503611 PMCID: PMC10715442 DOI: 10.1089/ars.2023.0350] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 05/28/2023] [Indexed: 07/29/2023]
Abstract
Significance: The remarkable geometry of the axon exposes it to unique challenges for survival and maintenance. Axonal degeneration is a feature of peripheral neuropathies, glaucoma, and traumatic brain injury, and an early event in neurodegenerative diseases. Since the discovery of Wallerian degeneration (WD), a molecular program that hijacks nicotinamide adenine dinucleotide (NAD+) metabolism for axonal self-destruction, the complex roles of NAD+ in axonal viability and disease have become research priority. Recent Advances: The discoveries of the protective Wallerian degeneration slow (WldS) and of sterile alpha and TIR motif containing 1 (SARM1) activation as the main instructive signal for WD have shed new light on the regulatory role of NAD+ in axonal degeneration in a growing number of neurological diseases. SARM1 has been characterized as a NAD+ hydrolase and sensor of NAD+ metabolism. The discovery of regulators of nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) proteostasis in axons, the allosteric regulation of SARM1 by NAD+ and NMN, and the existence of clinically relevant windows of action of these signals has opened new opportunities for therapeutic interventions, including SARM1 inhibitors and modulators of NAD+ metabolism. Critical Issues: Events upstream and downstream of SARM1 remain unclear. Furthermore, manipulating NAD+ metabolism, an overdetermined process crucial in cell survival, for preventing the degeneration of the injured axon may be difficult and potentially toxic. Future Directions: There is a need for clarification of the distinct roles of NAD+ metabolism in axonal maintenance as contrasted to WD. There is also a need to better understand the role of NAD+ metabolism in axonal endangerment in neuropathies, diseases of the white matter, and the early stages of neurodegenerative diseases of the central nervous system. Antioxid. Redox Signal. 39, 1167-1184.
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Affiliation(s)
| | - Vassilis E. Koliatsos
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Neurology, and Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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20
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Helbing DL, Kirkpatrick JM, Reuter M, Bischoff J, Stockdale A, Carlstedt A, Cirri E, Bauer R, Morrison H. Proteomic analysis of peripheral nerve myelin during murine aging. Front Cell Neurosci 2023; 17:1214003. [PMID: 37964793 PMCID: PMC10642449 DOI: 10.3389/fncel.2023.1214003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 10/09/2023] [Indexed: 11/16/2023] Open
Abstract
Aging of the peripheral nervous system (PNS) is associated with structural and functional changes that lead to a reduction in regenerative capacity and the development of age-related peripheral neuropathy. Myelin is central to maintaining physiological peripheral nerve function and differences in myelin maintenance, degradation, formation and clearance have been suggested to contribute to age-related PNS changes. Recent proteomic studies have elucidated the complex composition of the total myelin proteome in health and its changes in neuropathy models. However, changes in the myelin proteome of peripheral nerves during aging have not been investigated. Here we show that the proteomes of myelin fractions isolated from young and old nerves show only subtle changes. In particular, we found that the three most abundant peripheral myelin proteins (MPZ, MBP, and PRX) do not change in old myelin fractions. We also show a tendency for high-abundance myelin proteins other than these three to be downregulated, with only a small number of ribosome-related proteins significantly downregulated and extracellular matrix proteins such as collagens upregulated. In addition, we illustrate that the peripheral nerve myelin proteome reported in this study is suitable for assessing myelin degradation and renewal during peripheral nerve degeneration and regeneration. Our results suggest that the peripheral nerve myelin proteome is relatively stable and undergoes only subtle changes in composition during mouse aging. We proffer the resultant dataset as a resource and starting point for future studies aimed at investigating peripheral nerve myelin during aging. Said datasets are available in the PRIDE archive under the identifier PXD040719 (aging myelin proteome) and PXD041026 (sciatic nerve injury proteome).
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Affiliation(s)
- Dario Lucas Helbing
- Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany
- Department of Psychiatry and Psychotherapy, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
- Center for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health (C-I-R-C), Jena-Magdeburg-Halle, Germany
- German Center for Mental Health (DZPG), Jena, Germany
- Institute of Molecular Cell Biology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
| | | | - Michael Reuter
- Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany
| | - Julia Bischoff
- Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany
| | - Amy Stockdale
- Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany
| | | | - Emilio Cirri
- Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany
| | - Reinhard Bauer
- Institute of Molecular Cell Biology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
| | - Helen Morrison
- Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany
- Faculty of Biological Sciences, Friedrich Schiller University Jena, Jena, Germany
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21
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Oliveira JT, Yanick C, Wein N, Gomez Limia CE. Neuron-Schwann cell interactions in peripheral nervous system homeostasis, disease, and preclinical treatment. Front Cell Neurosci 2023; 17:1248922. [PMID: 37900588 PMCID: PMC10600466 DOI: 10.3389/fncel.2023.1248922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 09/19/2023] [Indexed: 10/31/2023] Open
Abstract
Schwann cells (SCs) have a critical role in the peripheral nervous system. These cells are able to support axons during homeostasis and after injury. However, mutations in genes associated with the SCs repair program or myelination result in dysfunctional SCs. Several neuropathies such as Charcot-Marie-Tooth (CMT) disease, diabetic neuropathy and Guillain-Barré syndrome show abnormal SC functions and an impaired regeneration process. Thus, understanding SCs-axon interaction and the nerve environment in the context of homeostasis as well as post-injury and disease onset is necessary. Several neurotrophic factors, cytokines, and regulators of signaling pathways associated with proliferation, survival and regeneration are involved in this process. Preclinical studies have focused on the discovery of therapeutic targets for peripheral neuropathies and injuries. To study the effect of new therapeutic targets, modeling neuropathies and peripheral nerve injuries (PNIs) in vitro and in vivo are useful tools. Furthermore, several in vitro protocols have been designed using SCs and neuron cell lines to evaluate these targets in the regeneration process. SCs lines have been used to generate effective myelinating SCs without success. Alternative options have been investigated using direct conversion from somatic cells to SCs or SCs derived from pluripotent stem cells to generate functional SCs. This review will go over the advantages of these systems and the problems associated with them. In addition, there have been challenges in establishing adequate and reproducible protocols in vitro to recapitulate repair SC-neuron interactions observed in vivo. So, we also discuss the mechanisms of repair SCs-axon interactions in the context of peripheral neuropathies and nerve injury (PNI) in vitro and in vivo. Finally, we summarize current preclinical studies evaluating transgenes, drug, and novel compounds with translational potential into clinical studies.
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Affiliation(s)
| | | | - Nicolas Wein
- Center for Gene Therapy, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
- Department of Pediatrics, The Ohio State University, Columbus, OH, United States
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22
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Mayrhofer F, Hanson AM, Navedo MF, Xiang YK, Soulika AM, Deng W, Chechneva OV. Transfer of nuclear and ribosomal material from Sox10-lineage cells to neurons in the mouse brain. J Exp Med 2023; 220:e20221632. [PMID: 37067791 PMCID: PMC10114922 DOI: 10.1084/jem.20221632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 02/22/2023] [Accepted: 03/27/2023] [Indexed: 04/18/2023] Open
Abstract
Material transfer is an essential form of intercellular communication to exchange information and resources between cells. Material transfer between neurons and from glia to neurons has been demonstrated to support neuronal survival and activity. Understanding the extent of material transfer in the healthy nervous system is limited. Here we report that in the mouse central nervous system (CNS), neurons receive nuclear and ribosomal material of Sox10-lineage cell (SOL) origin. We show that transfer of SOL-derived material to neurons is region dependent, establishes during postnatal brain maturation, and dynamically responds to LPS-induced neuroinflammation in the adult mouse brain. We identified satellite oligodendrocyte-neuron pairs with loss of plasma membrane integrity between nuclei, suggesting direct material transfer. Together, our findings provide evidence of regionally coordinated transfer of SOL-derived nuclear and ribosomal material to neurons in the mouse CNS, with potential implications for the understanding and modulation of neuronal function and treatment of neurological disorders.
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Affiliation(s)
- Florian Mayrhofer
- Institute for Pediatric Regenerative Medicine, Shriners Children’s Northern California, Sacramento, CA, USA
| | - Angela M. Hanson
- Institute for Pediatric Regenerative Medicine, Shriners Children’s Northern California, Sacramento, CA, USA
| | - Manuel F. Navedo
- Department of Pharmacology, University of California, Davis, Davis, CA, USA
| | - Yang K. Xiang
- Department of Pharmacology, University of California, Davis, Davis, CA, USA
- Northern California Health Care System, Mather, CA, USA
| | - Athena M. Soulika
- Institute for Pediatric Regenerative Medicine, Shriners Children’s Northern California, Sacramento, CA, USA
- Department of Dermatology, University of California, Davis, Sacramento, CA, USA
| | - Wenbin Deng
- Institute for Pediatric Regenerative Medicine, Shriners Children’s Northern California, Sacramento, CA, USA
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA, USA
- School of Pharmaceutical Sciences, Shenzhen Campus of Sun Yat-sen University, Guangdong, China
| | - Olga V. Chechneva
- Institute for Pediatric Regenerative Medicine, Shriners Children’s Northern California, Sacramento, CA, USA
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA, USA
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23
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Pluchino S, Prasad P. Oligodendroglia-to-neuron material transfer lights up the mouse CNS. J Exp Med 2023; 220:e20230489. [PMID: 37078982 PMCID: PMC10125899 DOI: 10.1084/jem.20230489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/21/2023] Open
Abstract
Intercellular material transfer in the central nervous system (CNS) supports neuronal survival and activity. Mayrhofer et al. (2023. J. Exp. Med.https://doi.org/10.1084/jem.20221632) characterize extensive regionally coordinated transfer of oligodendroglial ribosomal and nuclear material toward neurons, linked to satellite oligodendrocyte-neuron pairs in the mouse CNS.
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Affiliation(s)
- Stefano Pluchino
- Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, UK
| | - Pranathi Prasad
- Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, UK
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24
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Chen H, Xu Y, Wang W, Deng R, Li Z, Xie S, Jiao J. Assessment of Lumbosacral Nerve Roots in Patients with Type 2 Diabetic Peripheral Neuropathy Using Diffusion Tensor Imaging. Brain Sci 2023; 13:brainsci13050828. [PMID: 37239300 DOI: 10.3390/brainsci13050828] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/09/2023] [Accepted: 05/18/2023] [Indexed: 05/28/2023] Open
Abstract
BACKGROUND Diffusion tensor imaging (DTI) has found clinical applications in the evaluation of the central nervous system and has been extensively used to image peripheral neuropathy. However, few studies have focused on lumbosacral nerve root fiber damage in diabetic peripheral neuropathy (DPN). The aim of the study was to evaluate whether DTI of the lumbosacral nerve roots can be used to detect DPN. METHODS Thirty-two type 2 diabetic patients with DPN and thirty healthy controls (HCs) were investigated with a 3T MRI scanner. DTI with tractography of the L4, L5, and S1 nerve roots was performed. Anatomical fusion with the axial T2 sequences was used to provide correlating anatomical information. Mean fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were measured from tractography images and compared between groups. Diagnostic value was assessed using receiver operating characteristic (ROC) analysis. The Pearson correlation coefficient was used to explore the correlation between DTI parameters and clinical data and the nerve conduction study (NCS) in the DPN group. RESULTS In the DPN group, FA was decreased (p < 0.001) and ADC was increased (p < 0.001) compared with the values of the HC group. FA displayed the best diagnostic accuracy, with an area under the ROC curve of 0.716. ADC was positively correlated with HbA1c level (r = 0.379, p = 0.024) in the DPN group. CONCLUSIONS DTI of lumbosacral nerve roots demonstrates appreciable diagnostic accuracy in patients with DPN.
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Affiliation(s)
- He Chen
- Department of Radiology, Peking University China-Japan Friendship School of Clinical Medicine, Yinghua Street 2, Chaoyang District, Beijing 100029, China
| | - Yanyan Xu
- Department of Radiology, China-Japan Friendship Hospital, Yinghua Street 2, Chaoyang District, Beijing 100029, China
| | - Wei Wang
- Department of Neurology, China-Japan Friendship Hospital, Yinghua Street 2, Chaoyang District, Beijing 100029, China
| | - Ruifen Deng
- Department of Endocrinology, China-Japan Friendship Hospital, Yinghua Street 2, Chaoyang District, Beijing 100029, China
| | - Zhaoqing Li
- Department of Endocrinology, China-Japan Friendship Hospital, Yinghua Street 2, Chaoyang District, Beijing 100029, China
| | - Sheng Xie
- Department of Radiology, Peking University China-Japan Friendship School of Clinical Medicine, Yinghua Street 2, Chaoyang District, Beijing 100029, China
| | - Jinsong Jiao
- Department of Neurology, China-Japan Friendship Hospital, Yinghua Street 2, Chaoyang District, Beijing 100029, China
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25
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Deng H, Li B, Shen Q, Zhang C, Kuang L, Chen R, Wang S, Ma Z, Li G. Mechanisms of diabetic foot ulceration: A review. J Diabetes 2023; 15:299-312. [PMID: 36891783 PMCID: PMC10101842 DOI: 10.1111/1753-0407.13372] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 01/23/2023] [Accepted: 02/16/2023] [Indexed: 03/10/2023] Open
Abstract
Diabetic foot ulcers (DFUs) are associated with complex pathogenic factors and are considered a serious complication of diabetes. The potential mechanisms underlying DFUs have been increasingly investigated. Previous studies have focused on the three aspects of diabetic peripheral vascular disease, neuropathy, and wound infections. With advances in technology, researchers have been gradually conducting studies using immune cells, endothelial cells, keratinocytes, and fibroblasts, as they are involved in wound healing. It has been reported that the upregulation or downregulation of molecular signaling pathways is essential for the healing of DFUs. With a recent increase in the awareness of epigenetics, its regulatory role in wound healing has become a much sought-after trend in the treatment of DFUs. This review focuses on four aspects involved in the pathogenesis of DFUs: physiological and pathological mechanisms, cellular mechanisms, molecular signaling pathway mechanisms, and epigenetics. Given the challenge in the treatment of DFUs, we are hopeful that our review will provide new ideas for peers.
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Affiliation(s)
- Haibo Deng
- Department of Wound Repair, Liyuan Hospital Affiliated to Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - Binghui Li
- Department of Wound Repair, Liyuan Hospital Affiliated to Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - Qian Shen
- School of Foreign StudiesZhongnan University of Economics and LawWuhanHubeiChina
| | - Chenchen Zhang
- Department of Wound Repair, Liyuan Hospital Affiliated to Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - Liwen Kuang
- Department of Wound Repair, Liyuan Hospital Affiliated to Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - Ran Chen
- Department of Wound Repair, Liyuan Hospital Affiliated to Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - SiYuan Wang
- Department of Wound Repair, Liyuan Hospital Affiliated to Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - ZhiQiang Ma
- Department of Wound Repair, Liyuan Hospital Affiliated to Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - Gongchi Li
- Department of Hand Surgery, Union Hospital affiliated to Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
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26
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Bourke AM, Schwarz A, Schuman EM. De-centralizing the Central Dogma: mRNA translation in space and time. Mol Cell 2023; 83:452-468. [PMID: 36669490 DOI: 10.1016/j.molcel.2022.12.030] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/16/2022] [Accepted: 12/28/2022] [Indexed: 01/20/2023]
Abstract
As our understanding of the cell interior has grown, we have come to appreciate that most cellular operations are localized, that is, they occur at discrete and identifiable locations or domains. These cellular domains contain enzymes, machines, and other components necessary to carry out and regulate these localized operations. Here, we review these features of one such operation: the localization and translation of mRNAs within subcellular compartments observed across cell types and organisms. We describe the conceptual advantages and the "ingredients" and mechanisms of local translation. We focus on the nature and features of localized mRNAs, how they travel and get localized, and how this process is regulated. We also evaluate our current understanding of protein synthesis machines (ribosomes) and their cadre of regulatory elements, that is, the translation factors.
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Affiliation(s)
- Ashley M Bourke
- Max Planck Institute for Brain Research, Max von Laue Strasse 4, 60438 Frankfurt, Germany
| | - Andre Schwarz
- Max Planck Institute for Brain Research, Max von Laue Strasse 4, 60438 Frankfurt, Germany
| | - Erin M Schuman
- Max Planck Institute for Brain Research, Max von Laue Strasse 4, 60438 Frankfurt, Germany.
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27
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Pinho-Correia LM, Prokop A. Maintaining essential microtubule bundles in meter-long axons: a role for local tubulin biogenesis? Brain Res Bull 2023; 193:131-145. [PMID: 36535305 DOI: 10.1016/j.brainresbull.2022.12.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 12/12/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
Axons are the narrow, up-to-meter long cellular processes of neurons that form the biological cables wiring our nervous system. Most axons must survive for an organism's lifetime, i.e. up to a century in humans. Axonal maintenance depends on loose bundles of microtubules that run without interruption all along axons. The continued turn-over and the extension of microtubule bundles during developmental, regenerative or plastic growth requires the availability of α/β-tubulin heterodimers up to a meter away from the cell body. The underlying regulation in axons is poorly understood and hardly features in past and contemporary research. Here we discuss potential mechanisms, particularly focussing on the possibility of local tubulin biogenesis in axons. Current knowledge might suggest that local translation of tubulin takes place in axons, but far less is known about the post-translational machinery of tubulin biogenesis involving three chaperone complexes: prefoldin, CCT and TBC. We discuss functional understanding of these chaperones from a range of model organisms including yeast, plants, flies and mice, and explain what is known from human diseases. Microtubules across species depend on these chaperones, and they are clearly required in the nervous system. However, most chaperones display a high degree of functional pleiotropy, partly through independent functions of individual subunits outside their complexes, thus posing a challenge to experimental studies. Notably, we found hardly any studies that investigate their presence and function particularly in axons, thus highlighting an important gap in our understanding of axon biology and pathology.
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Affiliation(s)
- Liliana Maria Pinho-Correia
- The University of Manchester, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biology, Manchester, UK
| | - Andreas Prokop
- The University of Manchester, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biology, Manchester, UK.
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28
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Gale JR, Gedeon JY, Donnelly CJ, Gold MS. Local translation in primary afferents and its contribution to pain. Pain 2022; 163:2302-2314. [PMID: 35438669 PMCID: PMC9579217 DOI: 10.1097/j.pain.0000000000002658] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 04/08/2022] [Indexed: 02/06/2023]
Abstract
ABSTRACT Chronic pain remains a significant problem due to its prevalence, impact, and limited therapeutic options. Progress in addressing chronic pain is dependent on a better understanding of underlying mechanisms. Although the available evidence suggests that changes within the central nervous system contribute to the initiation and maintenance of chronic pain, it also suggests that the primary afferent plays a critical role in all phases of the manifestation of chronic pain in most of those who suffer. Most notable among the changes in primary afferents is an increase in excitability or sensitization. A number of mechanisms have been identified that contribute to primary afferent sensitization with evidence for both increases in pronociceptive signaling molecules, such as voltage-gated sodium channels, and decreases in antinociceptive signaling molecules, such as voltage-dependent or calcium-dependent potassium channels. Furthermore, these changes in signaling molecules seem to reflect changes in gene expression as well as posttranslational processing. A mechanism of sensitization that has received far less attention, however, is the local or axonal translation of these signaling molecules. A growing body of evidence indicates that this process not only is dynamically regulated but also contributes to the initiation and maintenance of chronic pain. Here, we review the biology of local translation in primary afferents and its relevance to pain pathobiology.
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Affiliation(s)
- Jenna R Gale
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
| | - Jeremy Y Gedeon
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
| | | | - Michael S Gold
- Corresponding author: Michael S Gold, PhD, Department of Neurobiology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, P: 412-383-5367,
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29
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Di Liegro CM, Schiera G, Schirò G, Di Liegro I. RNA-Binding Proteins as Epigenetic Regulators of Brain Functions and Their Involvement in Neurodegeneration. Int J Mol Sci 2022; 23:ijms232314622. [PMID: 36498959 PMCID: PMC9739182 DOI: 10.3390/ijms232314622] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 11/18/2022] [Accepted: 11/22/2022] [Indexed: 11/25/2022] Open
Abstract
A central aspect of nervous system development and function is the post-transcriptional regulation of mRNA fate, which implies time- and site-dependent translation, in response to cues originating from cell-to-cell crosstalk. Such events are fundamental for the establishment of brain cell asymmetry, as well as of long-lasting modifications of synapses (long-term potentiation: LTP), responsible for learning, memory, and higher cognitive functions. Post-transcriptional regulation is in turn dependent on RNA-binding proteins that, by recognizing and binding brief RNA sequences, base modifications, or secondary/tertiary structures, are able to control maturation, localization, stability, and translation of the transcripts. Notably, most RBPs contain intrinsically disordered regions (IDRs) that are thought to be involved in the formation of membrane-less structures, probably due to liquid-liquid phase separation (LLPS). Such structures are evidenced as a variety of granules that contain proteins and different classes of RNAs. The other side of the peculiar properties of IDRs is, however, that, under altered cellular conditions, they are also prone to form aggregates, as observed in neurodegeneration. Interestingly, RBPs, as part of both normal and aggregated complexes, are also able to enter extracellular vesicles (EVs), and in doing so, they can also reach cells other than those that produced them.
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Affiliation(s)
- Carlo Maria Di Liegro
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche) (STEBICEF), University of Palermo, 90128 Palermo, Italy
| | - Gabriella Schiera
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche) (STEBICEF), University of Palermo, 90128 Palermo, Italy
| | - Giuseppe Schirò
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (Dipartimento di Biomedicina, Neuroscienze e Diagnostica Avanzata) (Bi.N.D.), University of Palermo, 90127 Palermo, Italy
| | - Italia Di Liegro
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (Dipartimento di Biomedicina, Neuroscienze e Diagnostica Avanzata) (Bi.N.D.), University of Palermo, 90127 Palermo, Italy
- Correspondence: ; Tel.: +39-091-238-97 (ext. 415/446)
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30
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Ribosomes and Ribosomal Proteins Promote Plasticity and Stemness Induction in Glioma Cells via Reprogramming. Cells 2022; 11:cells11142142. [PMID: 35883585 PMCID: PMC9323835 DOI: 10.3390/cells11142142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 07/01/2022] [Accepted: 07/05/2022] [Indexed: 02/04/2023] Open
Abstract
Glioblastoma multiforme (GBM) is a lethal tumor that develops in the adult brain. Despite advances in therapeutic strategies related to surgical resection and chemo-radiotherapy, the overall survival of patients with GBM remains unsatisfactory. Genetic research on mutation, amplification, and deletion in GBM cells is important for understanding the biological aggressiveness, diagnosis, and prognosis of GBM. However, the efficacy of drugs targeting the genetic abnormalities in GBM cells is limited. Investigating special microenvironments that induce chemo-radioresistance in GBM cells is critical to improving the survival and quality of life of patients with GBM. GBM cells acquire and maintain stem-cell-like characteristics via their intrinsic potential and extrinsic factors from their special microenvironments. The acquisition of stem-cell-like phenotypes and aggressiveness may be referred to as a reprogramming of GBM cells. In addition to protein synthesis, deregulation of ribosome biogenesis is linked to several diseases including cancer. Ribosomal proteins possess both tumor-promotive and -suppressive functions as extra-ribosomal functions. Incorporation of ribosomes and overexpression of ribosomal protein S6 reprogram and induce stem-cell-like phenotypes in GBM cells. Herein, we review recent literature and our published data on the acquisition of aggressiveness by GBM and discuss therapeutic options through reprogramming.
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Hide T, Shibahara I, Inukai M, Shigeeda R, Shirakawa Y, Jono H, Shinojima N, Mukasa A, Kumabe T. Ribosomal proteins induce stem cell-like characteristics in glioma cells as an "extra-ribosomal function". Brain Tumor Pathol 2022; 39:51-56. [PMID: 35508789 DOI: 10.1007/s10014-022-00434-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 04/21/2022] [Indexed: 12/15/2022]
Abstract
The characteristic features of plasticity and heterogeneity in glioblastoma (GB) cells cause therapeutic difficulties. GB cells are exposed to various stimuli from the tumor microenvironment and acquire the potential to resist chemoradiotherapy. To investigate how GB cells acquire stem cell-like phenotypes, we focused on ribosomal proteins, because ribosome incorporation has been reported to induce stem cell-like phenotypes in somatic cells. Furthermore, dysregulation of ribosome biogenesis has been reported in several types of cancer. We focused on ribosomal protein S6, which promotes sphere-forming ability and stem cell marker expression in GB cells. We expect that investigation of dysregulation of ribosome biogenesis and extra-ribosomal function in GB will provide new insights about the plasticity, heterogeneity, and therapeutic resistance of GB cells, which can potentially lead to revolutionary therapeutic strategies.
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Affiliation(s)
- Takuichiro Hide
- Department of Neurosurgery, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.
| | - Ichiyo Shibahara
- Department of Neurosurgery, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Madoka Inukai
- Department of Neurosurgery, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Ryota Shigeeda
- Department of Neurosurgery, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Yuki Shirakawa
- Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 1-1-1 Honjo, chuo-ku, Kumamoto, 860-8556, Japan
| | - Hirofumi Jono
- Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 1-1-1 Honjo, chuo-ku, Kumamoto, 860-8556, Japan
| | - Naoki Shinojima
- Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 850-8556, Japan
| | - Akitake Mukasa
- Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 850-8556, Japan
| | - Toshihiro Kumabe
- Department of Neurosurgery, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
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Ahmad S, Srivastava RK, Singh P, Naik UP, Srivastava AK. Role of Extracellular Vesicles in Glia-Neuron Intercellular Communication. Front Mol Neurosci 2022; 15:844194. [PMID: 35493327 PMCID: PMC9043804 DOI: 10.3389/fnmol.2022.844194] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 02/23/2022] [Indexed: 11/13/2022] Open
Abstract
Cross talk between glia and neurons is crucial for a variety of biological functions, ranging from nervous system development, axonal conduction, synaptic transmission, neural circuit maturation, to homeostasis maintenance. Extracellular vesicles (EVs), which were initially described as cellular debris and were devoid of biological function, are now recognized as key components in cell-cell communication and play a critical role in glia-neuron communication. EVs transport the proteins, lipids, and nucleic acid cargo in intercellular communication, which alters target cells structurally and functionally. A better understanding of the roles of EVs in glia-neuron communication, both in physiological and pathological conditions, can aid in the discovery of novel therapeutic targets and the development of new biomarkers. This review aims to demonstrate that different types of glia and neuronal cells secrete various types of EVs, resulting in specific functions in intercellular communications.
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Affiliation(s)
- Shahzad Ahmad
- Department of Medical Elementology and Toxicology, Jamia Hamdard University, New Delhi, India
| | - Rohit K. Srivastava
- Department of Pediatric Surgery, Texas Children’s Hospital, Houston, TX, United States
- M.E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, United States
| | - Pratibha Singh
- Department of Biochemistry and Cell Biology, Biosciences Research Collaborative, Rice University, Houston, TX, United States
| | - Ulhas P. Naik
- Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Cardeza Foundation for Hematologic Research, Philadelphia, PA, United States
| | - Amit K. Srivastava
- Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Cardeza Foundation for Hematologic Research, Philadelphia, PA, United States
- *Correspondence: Amit K. Srivastava,
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Guo Y, Gil Z. The Role of Extracellular Vesicles in Cancer-Nerve Crosstalk of the Peripheral Nervous System. Cells 2022; 11:cells11081294. [PMID: 35455973 PMCID: PMC9027707 DOI: 10.3390/cells11081294] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 03/30/2022] [Accepted: 04/05/2022] [Indexed: 02/06/2023] Open
Abstract
Although the pathogenic operations of cancer–nerve crosstalk (e.g., neuritogenesis, neoneurogensis, and perineural invasion—PNI) in the peripheral nervous system (PNS) during tumorigenesis, as well as the progression of all cancer types is continuing to emerge as an area of unique scientific interest and study, extensive, wide-ranging, and multidisciplinary investigations still remain fragmented and unsystematic. This is especially so in regard to the roles played by extracellular vesicles (EVs), which are lipid bilayer-enclosed nano- to microsized particles that carry multiple-function molecular cargos, facilitate intercellular communication in diverse processes. Accordingly, the biological significance of EVs has been greatly elevated in recent years, as there is strong evidence that they could contribute to important and possibly groundbreaking diagnostic and therapeutic innovations. This can be achieved and the pace of discoveries accelerated through cross-pollination from existing knowledge and studies regarding nervous system physiology and pathology, as well as thoroughgoing collaborations between oncologists, neurobiologists, pathologists, clinicians, and researchers. This article offers an overview of current and recent past investigations on the roles of EVs in cancer–nerve crosstalk, as well as in neural development, physiology, inflammation, injury, and regeneration in the PNS. By highlighting the mechanisms involved in physiological and noncancerous pathological cellular crosstalk, we provide hints that may inspire additional translational studies on cancer–nerve interplay.
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Affiliation(s)
- Yuanning Guo
- Rappaport Family Institute for Research in the Medical Sciences, Technion—Israel Institute of Technology, Haifa 31096, Israel;
| | - Ziv Gil
- Rappaport Family Institute for Research in the Medical Sciences, Technion—Israel Institute of Technology, Haifa 31096, Israel;
- Head and Neck Institute, The Holy Family Hospital Nazareth, Nazareth 1641100, Israel
- Correspondence: ; Tel.: +972-4-854-2480
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Contreras E, Bolívar S, Navarro X, Udina E. New insights into peripheral nerve regeneration: The role of secretomes. Exp Neurol 2022; 354:114069. [DOI: 10.1016/j.expneurol.2022.114069] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 02/05/2022] [Accepted: 04/03/2022] [Indexed: 11/04/2022]
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Wan R, Hussain A, Behfar A, Moran SL, Zhao C. The Therapeutic Potential of Exosomes in Soft Tissue Repair and Regeneration. Int J Mol Sci 2022; 23:ijms23073869. [PMID: 35409228 PMCID: PMC8998690 DOI: 10.3390/ijms23073869] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/28/2022] [Accepted: 03/28/2022] [Indexed: 12/12/2022] Open
Abstract
Soft tissue defects are common following trauma and tumor extirpation. These injuries can result in poor functional recovery and lead to a diminished quality of life. The healing of skin and muscle is a complex process that, at present, leads to incomplete recovery and scarring. Regenerative medicine may offer the opportunity to improve the healing process and functional outcomes. Barriers to regenerative strategies have included cost, regulatory hurdles, and the need for cell-based therapies. In recent years, exosomes, or extracellular vesicles, have gained tremendous attention in the field of soft tissue repair and regeneration. These nanosized extracellular particles (30-140 nm) can break the cellular boundaries, as well as facilitate intracellular signal delivery in various regenerative physiologic and pathologic processes. Existing studies have established the potential of exosomes in regenerating tendons, skeletal muscles, and peripheral nerves through different mechanisms, including promoting myogenesis, increasing tenocyte differentiation and enhancing neurite outgrowth, and the proliferation of Schwann cells. These exosomes can be stored for immediate use in the operating room, and can be produced cost efficiently. In this article, we critically review the current advances of exosomes in soft tissue (tendons, skeletal muscles, and peripheral nerves) healing. Additionally, new directions for clinical applications in the future will be discussed.
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Affiliation(s)
- Rou Wan
- Division of Plastic Surgery, Mayo Clinic, Rochester, MN 55905, USA; (R.W.); (A.H.); (S.L.M.)
| | - Arif Hussain
- Division of Plastic Surgery, Mayo Clinic, Rochester, MN 55905, USA; (R.W.); (A.H.); (S.L.M.)
| | - Atta Behfar
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA;
- Van Cleve Cardiac Regenerative Medicine Program, Center for Regenerative Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Steven L. Moran
- Division of Plastic Surgery, Mayo Clinic, Rochester, MN 55905, USA; (R.W.); (A.H.); (S.L.M.)
| | - Chunfeng Zhao
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA
- Correspondence:
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Dastidar SG, Nair D. A Ribosomal Perspective on Neuronal Local Protein Synthesis. Front Mol Neurosci 2022; 15:823135. [PMID: 35283723 PMCID: PMC8904363 DOI: 10.3389/fnmol.2022.823135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 01/17/2022] [Indexed: 11/15/2022] Open
Abstract
Continued mRNA translation and protein production are critical for various neuronal functions. In addition to the precise sorting of proteins from cell soma to distant locations, protein synthesis allows a dynamic remodeling of the local proteome in a spatially variable manner. This spatial heterogeneity of protein synthesis is shaped by several factors such as injury, guidance cues, developmental cues, neuromodulators, and synaptic activity. In matured neurons, thousands of synapses are non-uniformly distributed throughout the dendritic arbor. At any given moment, the activity of individual synapses varies over a wide range, giving rise to the variability in protein synthesis. While past studies have primarily focused on the translation factors or the identity of translated mRNAs to explain the source of this variation, the role of ribosomes in this regard continues to remain unclear. Here, we discuss how several stochastic mechanisms modulate ribosomal functions, contributing to the variability in neuronal protein expression. Also, we point out several underexplored factors such as local ion concentration, availability of tRNA or ATP during translation, and molecular composition and organization of a compartment that can influence protein synthesis and its variability in neurons.
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Bischoff JP, Schulz A, Morrison H. The role of exosomes in inter-cellular and inter-organ communication of the peripheral nervous system. FEBS Lett 2022; 596:655-664. [PMID: 34990014 DOI: 10.1002/1873-3468.14274] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 12/09/2021] [Accepted: 12/23/2021] [Indexed: 11/11/2022]
Abstract
Exosomes, nano-sized extracellular vesicles, are produced via the endosomal pathway and released in the extracellular space upon fusion of multivesicular bodies with the plasma membrane. Recent evidence shows that these extracellular vesicles play a key role in cell-to-cell communication. Exosomes transport bioactive proteins, messenger RNA (mRNAs) and microRNA (miRNAs) in an active form to adjacent cells or to distant organs. In this review, we focus on the role of exosomes in peripheral nerve maintenance and repair, as well as peripheral nerve/organ crosstalk, and discuss the potential benefits of exploiting exosomes for treating PNS injuries. In addition, we will highlight the emerging role of exosomes as new important vehicles for physiological systemic crosstalk failures, which could lead to organ dysfunction during neuroinflammation or aging.
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Affiliation(s)
- Julia Patricia Bischoff
- Leibniz Institute on Aging, Fritz Lipmann Institute, Beutenbergstrasse 11, 07745, Jena, Germany
| | - Alexander Schulz
- Leibniz Institute on Aging, Fritz Lipmann Institute, Beutenbergstrasse 11, 07745, Jena, Germany
| | - Helen Morrison
- Leibniz Institute on Aging, Fritz Lipmann Institute, Beutenbergstrasse 11, 07745, Jena, Germany.,Institute of Biochemistry and Biophysics, Friedrich-Schiller-University Jena, Faculty of Biological Sciences, Friedrich Schiller University Jena, Jena, Germany
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Jia L, Liao M, Mou A, Zheng Q, Yang W, Yu Z, Cui Y, Xia X, Qin Y, Chen M, Xiao B. Rheb-regulated mitochondrial pyruvate metabolism of Schwann cells linked to axon stability. Dev Cell 2021; 56:2980-2994.e6. [PMID: 34619097 DOI: 10.1016/j.devcel.2021.09.013] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 08/12/2021] [Accepted: 09/10/2021] [Indexed: 02/05/2023]
Abstract
The metabolic coupling of Schwann cells (SCs) and peripheral axons is poorly understood. Few molecules in SCs are known to regulate axon stability. Using SC-specific Rheb knockout mice, we demonstrate that Rheb-regulated mitochondrial pyruvate metabolism is critical for SC-mediated non-cell-autonomous regulation of peripheral axon stability. Rheb knockout suppresses pyruvate dehydrogenase (PDH) activity (independently of mTORC1) and shifts pyruvate metabolism toward lactate production in SCs. The increased lactate causes age-dependent peripheral axon degeneration, affecting peripheral nerve function. Lactate, as an energy substrate and a potential signaling molecule, enhanced neuronal mitochondrial metabolism and energy production of peripheral nerves. Albeit beneficial to injured peripheral axons in the short term, we show that persistently increased lactate metabolism of neurons enhances ROS production, eventually damaging mitochondria, neuroenergetics, and axon stability. This study highlights the complex roles of lactate metabolism to peripheral axons and the importance of lactate homeostasis in preserving peripheral nerves.
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Affiliation(s)
- Lanlan Jia
- Neuroscience & Metabolism Research, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Maoxing Liao
- Neuroscience & Metabolism Research, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Aidi Mou
- Neuroscience & Metabolism Research, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Quanzhen Zheng
- Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, People's Republic of China; Department of Biology, School of Life Sciences, Brain Research Center, Southern University of Science and Technology, Shenzhen 518000, People's Republic of China
| | - Wanchun Yang
- Neuroscience & Metabolism Research, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Zongyan Yu
- Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, People's Republic of China; Department of Biology, School of Life Sciences, Brain Research Center, Southern University of Science and Technology, Shenzhen 518000, People's Republic of China
| | - Yiyuan Cui
- Neuroscience & Metabolism Research, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Xiaoqiang Xia
- Neuroscience & Metabolism Research, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; Department of Biology, School of Life Sciences, Brain Research Center, Southern University of Science and Technology, Shenzhen 518000, People's Republic of China
| | - Yue Qin
- Neuroscience & Metabolism Research, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Mina Chen
- Neuroscience & Metabolism Research, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Bo Xiao
- Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, People's Republic of China; Department of Biology, School of Life Sciences, Brain Research Center, Southern University of Science and Technology, Shenzhen 518000, People's Republic of China.
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Das S, Vera M, Gandin V, Singer RH, Tutucci E. Intracellular mRNA transport and localized translation. Nat Rev Mol Cell Biol 2021; 22:483-504. [PMID: 33837370 PMCID: PMC9346928 DOI: 10.1038/s41580-021-00356-8] [Citation(s) in RCA: 184] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/25/2021] [Indexed: 02/08/2023]
Abstract
Fine-tuning cellular physiology in response to intracellular and environmental cues requires precise temporal and spatial control of gene expression. High-resolution imaging technologies to detect mRNAs and their translation state have revealed that all living organisms localize mRNAs in subcellular compartments and create translation hotspots, enabling cells to tune gene expression locally. Therefore, mRNA localization is a conserved and integral part of gene expression regulation from prokaryotic to eukaryotic cells. In this Review, we discuss the mechanisms of mRNA transport and local mRNA translation across the kingdoms of life and at organellar, subcellular and multicellular resolution. We also discuss the properties of messenger ribonucleoprotein and higher order RNA granules and how they may influence mRNA transport and local protein synthesis. Finally, we summarize the technological developments that allow us to study mRNA localization and local translation through the simultaneous detection of mRNAs and proteins in single cells, mRNA and nascent protein single-molecule imaging, and bulk RNA and protein detection methods.
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Affiliation(s)
- Sulagna Das
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, New York, NY, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, New York, NY, USA
| | - Maria Vera
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
| | | | - Robert H Singer
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, New York, NY, USA.
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, New York, NY, USA.
- Janelia Research Campus of the HHMI, Ashburn, VA, USA.
| | - Evelina Tutucci
- Systems Biology Lab, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
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Gamarra M, de la Cruz A, Blanco-Urrejola M, Baleriola J. Local Translation in Nervous System Pathologies. Front Integr Neurosci 2021; 15:689208. [PMID: 34276318 PMCID: PMC8279726 DOI: 10.3389/fnint.2021.689208] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 06/03/2021] [Indexed: 12/13/2022] Open
Abstract
Dendrites and axons can extend dozens to hundreds of centimeters away from the cell body so that a single neuron can sense and respond to thousands of stimuli. Thus, for an accurate function of dendrites and axons the neuronal proteome needs to be asymmetrically distributed within neurons. Protein asymmetry can be achieved by the transport of the protein itself or the transport of the mRNA that is then translated at target sites in neuronal processes. The latter transport mechanism implies local translation of localized mRNAs. The role of local translation in nervous system (NS) development and maintenance is well established, but recently there is growing evidence that this mechanism and its deregulation are also relevant in NS pathologies, including neurodegenerative diseases. For instance, upon pathological signals disease-related proteins can be locally synthesized in dendrites and axons. Locally synthesized proteins can exert their effects at or close to the site of translation, or they can be delivered to distal compartments like the nucleus and induce transcriptional responses that lead to neurodegeneration, nerve regeneration and other cell-wide responses. Relevant key players in the process of local protein synthesis are RNA binding proteins (RBPs), responsible for mRNA transport to neurites. Several neurological and neurodegenerative disorders, including amyotrophic lateral sclerosis or spinal motor atrophy, are characterized by mutations in genes encoding for RBPs and consequently mRNA localization and local translation are impaired. In other diseases changes in the local mRNA repertoire and altered local protein synthesis have been reported. In this review, we will discuss how deregulation of localized translation at different levels can contribute to the development and progression of nervous system pathologies.
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Affiliation(s)
- María Gamarra
- Laboratory of Local Translation in Neurons and Glia, Achucarro Basque Center for Neuroscience, Leioa, Spain.,Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU), Leioa, Spain
| | - Aida de la Cruz
- Laboratory of Local Translation in Neurons and Glia, Achucarro Basque Center for Neuroscience, Leioa, Spain.,Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU), Leioa, Spain
| | - Maite Blanco-Urrejola
- Laboratory of Local Translation in Neurons and Glia, Achucarro Basque Center for Neuroscience, Leioa, Spain.,Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU), Leioa, Spain.,Departamento de Biología Celular e Histología, Universidad del País Vasco (UPV/EHU), Leioa, Spain
| | - Jimena Baleriola
- Laboratory of Local Translation in Neurons and Glia, Achucarro Basque Center for Neuroscience, Leioa, Spain.,Departamento de Biología Celular e Histología, Universidad del País Vasco (UPV/EHU), Leioa, Spain.,Ikerbasque, Basque Foundation for Science, Bilbao, Spain
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Di Paolo A, Garat J, Eastman G, Farias J, Dajas-Bailador F, Smircich P, Sotelo-Silveira JR. Functional Genomics of Axons and Synapses to Understand Neurodegenerative Diseases. Front Cell Neurosci 2021; 15:686722. [PMID: 34248504 PMCID: PMC8267896 DOI: 10.3389/fncel.2021.686722] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Accepted: 06/02/2021] [Indexed: 01/02/2023] Open
Abstract
Functional genomics studies through transcriptomics, translatomics and proteomics have become increasingly important tools to understand the molecular basis of biological systems in the last decade. In most cases, when these approaches are applied to the nervous system, they are centered in cell bodies or somatodendritic compartments, as these are easier to isolate and, at least in vitro, contain most of the mRNA and proteins present in all neuronal compartments. However, key functional processes and many neuronal disorders are initiated by changes occurring far away from cell bodies, particularly in axons (axopathologies) and synapses (synaptopathies). Both neuronal compartments contain specific RNAs and proteins, which are known to vary depending on their anatomical distribution, developmental stage and function, and thus form the complex network of molecular pathways required for neuron connectivity. Modifications in these components due to metabolic, environmental, and/or genetic issues could trigger or exacerbate a neuronal disease. For this reason, detailed profiling and functional understanding of the precise changes in these compartments may thus yield new insights into the still intractable molecular basis of most neuronal disorders. In the case of synaptic dysfunctions or synaptopathies, they contribute to dozens of diseases in the human brain including neurodevelopmental (i.e., autism, Down syndrome, and epilepsy) as well as neurodegenerative disorders (i.e., Alzheimer's and Parkinson's diseases). Histological, biochemical, cellular, and general molecular biology techniques have been key in understanding these pathologies. Now, the growing number of omics approaches can add significant extra information at a high and wide resolution level and, used effectively, can lead to novel and insightful interpretations of the biological processes at play. This review describes current approaches that use transcriptomics, translatomics and proteomic related methods to analyze the axon and presynaptic elements, focusing on the relationship that axon and synapses have with neurodegenerative diseases.
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Affiliation(s)
- Andres Di Paolo
- Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable (IIBCE), Montevideo, Uruguay
- Departamento de Proteínas y Ácidos Nucleicos, Instituto de Investigaciones Biológicas Clemente Estable (IIBCE), Montevideo, Uruguay
| | - Joaquin Garat
- Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable (IIBCE), Montevideo, Uruguay
| | - Guillermo Eastman
- Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable (IIBCE), Montevideo, Uruguay
| | - Joaquina Farias
- Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable (IIBCE), Montevideo, Uruguay
- Polo de Desarrollo Universitario “Espacio de Biología Vegetal del Noreste”, Centro Universitario Regional Noreste, Universidad de la República (UdelaR), Tacuarembó, Uruguay
| | - Federico Dajas-Bailador
- School of Life Sciences, Medical School Building, University of Nottingham, Nottingham, United Kingdom
| | - Pablo Smircich
- Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable (IIBCE), Montevideo, Uruguay
- Laboratorio de Interacciones Moleculares, Facultad de Ciencias, Universidad de la República (UdelaR), Montevideo, Uruguay
| | - José Roberto Sotelo-Silveira
- Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable (IIBCE), Montevideo, Uruguay
- Departamento de Biología Celular y Molecular, Facultad de Ciencias, Universidad de la República (UdelaR), Montevideo, Uruguay
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Nagano S, Araki T. Axonal Transport and Local Translation of mRNA in Neurodegenerative Diseases. Front Mol Neurosci 2021; 14:697973. [PMID: 34194300 PMCID: PMC8236635 DOI: 10.3389/fnmol.2021.697973] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 05/25/2021] [Indexed: 12/13/2022] Open
Abstract
Since neurons have long neurites including axons, it is crucial for the axons to transport many intracellular substances such as proteins and mitochondria in order to maintain their morphology and function. In addition, mRNAs have also been shown to be transported within axons. RNA-binding proteins form complexes with mRNAs, and regulate transport of the mRNAs to axons, as well as locally translate them into proteins. Local translation of mRNAs actively occurs during the development and damage of neurons, and plays an important role in axon elongation, regeneration, and synapse formation. In recent years, it has been reported that impaired axonal transport and local translation of mRNAs may be involved in the pathogenesis of some neurodegenerative diseases. In this review, we discuss the significance of mRNA axonal transport and their local translation in amyotrophic lateral sclerosis/frontotemporal dementia, spinal muscular atrophy, Alzheimer’s disease, and fragile X syndrome.
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Affiliation(s)
- Seiichi Nagano
- Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Osaka, Japan.,Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
| | - Toshiyuki Araki
- Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
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43
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Kobayashi M, Zochodne DW. Diabetic polyneuropathy: Bridging the translational gap. J Peripher Nerv Syst 2021; 25:66-75. [PMID: 32573914 DOI: 10.1111/jns.12392] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/14/2020] [Accepted: 05/15/2020] [Indexed: 12/22/2022]
Abstract
Clinical trials for diabetic polyneuropathy (DPN) have failed to identify therapeutic impacts that have arrested or reversed the disorder, despite a long history. This review considers DPN in the context of a unique neurodegenerative disorder that targets peripheral neurons and their companion glial cells. The approach is to examine what cells, cell substructures, and pathways are implicated in causing DPN and how they might be addressed therapeutically. These include axonopathy, neuronopathy, hyperglycemia, polyol flux, advanced glycation endproduct (AGE)-receptor AGE signaling, growth factor disruption, abnormal insulin signaling, and abnormalities of other intrinsic neuron pathways. Mitochondrial dysfunction and lipid toxicity are largely delegated to the companion review in this issue by Stino and Feldman. Finally, the linkage between axon plasticity of cutaneous nerves, peripheral neuroregenerative pathways, and diabetes are discussed.
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Affiliation(s)
- Masaki Kobayashi
- Department of Neurology, Nissan Tamagawa Hospital, Tokyo, Japan.,Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Tokyo, Japan
| | - Douglas W Zochodne
- Division of Neurology and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada
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44
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Gomzikova MO, James V, Rizvanov AA. Mitochondria Donation by Mesenchymal Stem Cells: Current Understanding and Mitochondria Transplantation Strategies. Front Cell Dev Biol 2021; 9:653322. [PMID: 33898449 PMCID: PMC8058353 DOI: 10.3389/fcell.2021.653322] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 03/09/2021] [Indexed: 12/19/2022] Open
Abstract
The phenomenon of mitochondria donation is found in various tissues of humans and animals and is attracting increasing attention. To date, numerous studies have described the transfer of mitochondria from stem cells to injured cells, leading to increased ATP production, restoration of mitochondria function, and rescue of recipient cells from apoptosis. Mitochondria transplantation is considered as a novel therapeutic approach for the treatment of mitochondrial diseases and mitochondrial function deficiency. Mitochondrial dysfunction affects cells with high energy needs such as neural, skeletal muscle, heart, and liver cells and plays a crucial role in type 2 diabetes, as well as Parkinson's, Alzheimer's diseases, ischemia, stroke, cancer, and age-related disorders. In this review, we summarize recent findings in the field of mitochondria donation and mechanism of mitochondria transfer between cells. We review the existing clinical trials and discuss advantages and disadvantages of mitochondrial transplantation strategies based on the injection of stem cells, isolated functional mitochondria, or EVs containing mitochondria.
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Affiliation(s)
- Marina O Gomzikova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.,M.M. Shemyakin-Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia
| | - Victoria James
- School of Veterinary Medicine and Science, University of Nottingham, Nottingham, United Kingdom
| | - Albert A Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.,M.M. Shemyakin-Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia.,School of Veterinary Medicine and Science, University of Nottingham, Nottingham, United Kingdom
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45
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Di Paolo A, Farias J, Garat J, Macklin A, Ignatchenko V, Kislinger T, Sotelo Silveira J. Rat Sciatic Nerve Axoplasm Proteome Is Enriched with Ribosomal Proteins during Regeneration Processes. J Proteome Res 2021; 20:2506-2520. [PMID: 33793244 DOI: 10.1021/acs.jproteome.0c00980] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Axons are complex subcellular compartments that are extremely long in relation to cell bodies, especially in peripheral nerves. Many processes are required and regulated during axon injury, including anterograde and retrograde transport, glia-to-axon macromolecular transfer, and local axonal protein synthesis. Many in vitro omics approaches have been used to gain insight into these processes, but few have been applied in vivo. Here we adapted the osmotic ex vivo axoplasm isolation method and analyzed the adult rat sciatic-nerve-extruded axoplasm by label-free quantitative proteomics before and after injury. 2087 proteins groups were detected in the axoplasm, revealing translation machinery and microtubule-associated proteins as the most overrepresented biological processes. Ribosomal proteins (73) were detected in the uninjured axoplasm and increased their levels after injury but not within whole sciatic nerves. Meta-analysis showed that detected ribosomal proteins were present in in vitro axonal proteomes. Because local protein synthesis is important for protein localization, we were interested in detecting the most abundant newly synthesized axonal proteins in vivo. With an MS/MS-BONCAT approach, we detected 42 newly synthesized protein groups. Overall, our work indicates that proteomics profiling is useful for local axonal interrogation and suggests that ribosomal proteins may play an important role, especially during injury.
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Affiliation(s)
- Andres Di Paolo
- Departamento de Proteínas y Ácidos Nucleicos, IIBCE, 11600 Montevideo, Uruguay.,Departamento de Genómica, IIBCE, 11600 Montevideo, Uruguay
| | | | - Joaquin Garat
- Departamento de Genómica, IIBCE, 11600 Montevideo, Uruguay
| | - Andrew Macklin
- Princess Margaret Cancer Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada
| | - Vladimir Ignatchenko
- Princess Margaret Cancer Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada
| | - Thomas Kislinger
- Princess Margaret Cancer Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.,Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada
| | - José Sotelo Silveira
- Departamento de Genómica, IIBCE, 11600 Montevideo, Uruguay.,Departamento de Biología Celular y Molecular, Facultad de Ciencias, 11400 Montevideo, Uruguay
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46
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Dalla Costa I, Buchanan CN, Zdradzinski MD, Sahoo PK, Smith TP, Thames E, Kar AN, Twiss JL. The functional organization of axonal mRNA transport and translation. Nat Rev Neurosci 2021; 22:77-91. [PMID: 33288912 PMCID: PMC8161363 DOI: 10.1038/s41583-020-00407-7] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/26/2020] [Indexed: 12/13/2022]
Abstract
Axons extend for tremendously long distances from the neuronal soma and make use of localized mRNA translation to rapidly respond to different extracellular stimuli and physiological states. The locally synthesized proteins support many different functions in both developing and mature axons, raising questions about the mechanisms by which local translation is organized to ensure the appropriate responses to specific stimuli. Publications over the past few years have uncovered new mechanisms for regulating the axonal transport and localized translation of mRNAs, with several of these pathways converging on the regulation of cohorts of functionally related mRNAs - known as RNA regulons - that drive axon growth, axon guidance, injury responses, axon survival and even axonal mitochondrial function. Recent advances point to these different regulatory pathways as organizing platforms that allow the axon's proteome to be modulated to meet its physiological needs.
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Affiliation(s)
- Irene Dalla Costa
- Department of Biological Sciences, University of South Carolina, Columbia, SC, USA
| | - Courtney N Buchanan
- Department of Biological Sciences, University of South Carolina, Columbia, SC, USA
| | | | - Pabitra K Sahoo
- Department of Biological Sciences, University of South Carolina, Columbia, SC, USA
| | - Terika P Smith
- Department of Biological Sciences, University of South Carolina, Columbia, SC, USA
| | - Elizabeth Thames
- Department of Biological Sciences, University of South Carolina, Columbia, SC, USA
| | - Amar N Kar
- Department of Biological Sciences, University of South Carolina, Columbia, SC, USA
| | - Jeffery L Twiss
- Department of Biological Sciences, University of South Carolina, Columbia, SC, USA.
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Yousuf MS, Shiers SI, Sahn JJ, Price TJ. Pharmacological Manipulation of Translation as a Therapeutic Target for Chronic Pain. Pharmacol Rev 2021; 73:59-88. [PMID: 33203717 PMCID: PMC7736833 DOI: 10.1124/pharmrev.120.000030] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Dysfunction in regulation of mRNA translation is an increasingly recognized characteristic of many diseases and disorders, including cancer, diabetes, autoimmunity, neurodegeneration, and chronic pain. Approximately 50 million adults in the United States experience chronic pain. This economic burden is greater than annual costs associated with heart disease, cancer, and diabetes combined. Treatment options for chronic pain are inadequately efficacious and riddled with adverse side effects. There is thus an urgent unmet need for novel approaches to treating chronic pain. Sensitization of neurons along the nociceptive pathway causes chronic pain states driving symptoms that include spontaneous pain and mechanical and thermal hypersensitivity. More than a decade of preclinical research demonstrates that translational mechanisms regulate the changes in gene expression that are required for ongoing sensitization of nociceptive sensory neurons. This review will describe how key translation regulation signaling pathways, including the integrated stress response, mammalian target of rapamycin, AMP-activated protein kinase (AMPK), and mitogen-activated protein kinase-interacting kinases, impact the translation of different subsets of mRNAs. We then place these mechanisms of translation regulation in the context of chronic pain states, evaluate currently available therapies, and examine the potential for developing novel drugs. Considering the large body of evidence now published in this area, we propose that pharmacologically manipulating specific aspects of the translational machinery may reverse key neuronal phenotypic changes causing different chronic pain conditions. Therapeutics targeting these pathways could eventually be first-line drugs used to treat chronic pain disorders. SIGNIFICANCE STATEMENT: Translational mechanisms regulating protein synthesis underlie phenotypic changes in the sensory nervous system that drive chronic pain states. This review highlights regulatory mechanisms that control translation initiation and how to exploit them in treating persistent pain conditions. We explore the role of mammalian/mechanistic target of rapamycin and mitogen-activated protein kinase-interacting kinase inhibitors and AMPK activators in alleviating pain hypersensitivity. Modulation of eukaryotic initiation factor 2α phosphorylation is also discussed as a potential therapy. Targeting specific translation regulation mechanisms may reverse changes in neuronal hyperexcitability associated with painful conditions.
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Affiliation(s)
- Muhammad Saad Yousuf
- Center for Advanced Pain Studies, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas (M.S.Y., S.I.S., T.J.P.) and 4E Therapeutics Inc, Austin, Texas (J.J.S.)
| | - Stephanie I Shiers
- Center for Advanced Pain Studies, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas (M.S.Y., S.I.S., T.J.P.) and 4E Therapeutics Inc, Austin, Texas (J.J.S.)
| | - James J Sahn
- Center for Advanced Pain Studies, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas (M.S.Y., S.I.S., T.J.P.) and 4E Therapeutics Inc, Austin, Texas (J.J.S.)
| | - Theodore J Price
- Center for Advanced Pain Studies, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas (M.S.Y., S.I.S., T.J.P.) and 4E Therapeutics Inc, Austin, Texas (J.J.S.)
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48
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Alqurashi H, Ortega Asencio I, Lambert DW. The Emerging Potential of Extracellular Vesicles in Cell-Free Tissue Engineering and Regenerative Medicine. TISSUE ENGINEERING PART B-REVIEWS 2020; 27:530-538. [PMID: 33126845 DOI: 10.1089/ten.teb.2020.0222] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Extracellular vesicles (Evs) are membrane-enclosed vesicles secreted by all cell types that mediate cell-cell communication via their protein, lipid, carbohydrate, and nucleic acid (RNA, DNA) cargo. EVs are involved in a multitude of physiological processes, including development, cell differentiation, and angiogenesis, and have been implicated in tissue repair. Thus, they have been suggested to offer opportunities for the development of novel cell-free tissue engineering (TE) approaches. In this review, we provide an overview of current understanding and emerging applications of EVs in TE and address opportunities and challenges for clinical translation. In addition, we discuss systemic and local routes of delivery of EVs and the advantages and disadvantages of different biomaterials in providing a substrate for the sustained release of EVs in vivo. Impact statement Extracellular vesicles (EVs) are nanoscale, membrane-bound vesicles released by most, if not all, cells in the body. They are implicated in a wide range of physiological processes and diseases ranging from cancer to neurodegeneration, and hold huge potential as mediators of tissue regeneration. This has led to an explosion of interest in using EVs in a variety of tissue engineering applications. In this review, we provide an overview of current progress in the field and highlight the opportunities and challenges of harnessing the potential of EVs in regenerative medicine.
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Affiliation(s)
- Hatim Alqurashi
- School of Clinical Dentistry, The University of Sheffield, Sheffield, United Kingdom.,College of Dentistry, King Faisal University, Alhassa, Saudi Arabia
| | - Ilida Ortega Asencio
- School of Clinical Dentistry, The University of Sheffield, Sheffield, United Kingdom
| | - Daniel W Lambert
- School of Clinical Dentistry, The University of Sheffield, Sheffield, United Kingdom
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49
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Gonçalves NP, Yan Y, Ulrichsen M, Venø MT, Poulsen ET, Enghild JJ, Kjems J, Vægter CB. Modulation of Small RNA Signatures in Schwann-Cell-Derived Extracellular Vesicles by the p75 Neurotrophin Receptor and Sortilin. Biomedicines 2020; 8:E450. [PMID: 33114403 PMCID: PMC7694014 DOI: 10.3390/biomedicines8110450] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 10/20/2020] [Accepted: 10/22/2020] [Indexed: 12/12/2022] Open
Abstract
Schwann cells (SCs) are the main glial cells of the peripheral nervous system (PNS) and are known to be involved in various pathophysiological processes, such as diabetic neuropathy and nerve regeneration, through neurotrophin signaling. Such glial trophic support to axons, as well as neuronal survival/death signaling, has previously been linked to the p75 neurotrophin receptor (p75NTR) and its co-receptor Sortilin. Recently, SC-derived extracellular vesicles (EVs) were shown to be important for axon growth and nerve regeneration, but cargo of these glial cell-derived EVs has not yet been well-characterized. In this study, we aimed to characterize signatures of small RNAs in EVs derived from wild-type (WT) SCs and define differentially expressed small RNAs in EVs derived from SCs with genetic deletions of p75NTR (Ngfr-/-) or Sortilin (Sort1-/-). Using RNA sequencing, we identified a total of 366 miRNAs in EVs derived from WT SCs of which the most highly expressed are linked to the regulation of axonogenesis, axon guidance and axon extension, suggesting an involvement of SC EVs in axonal homeostasis. Signaling of SC EVs to non-neuronal cells was also suggested by the presence of several miRNAs important for regulation of the endothelial cell apoptotic process. Ablated p75NTR or sortilin expression in SCs translated into a set of differentially regulated tRNAs and miRNAs, with impact in autophagy and several cellular signaling pathways such as the phosphatidylinositol signaling system. With this work, we identified the global expression profile of small RNAs present in SC-derived EVs and provided evidence for a regulatory function of these vesicles on the homeostasis of other cell types of the PNS. Differentially identified miRNAs can pave the way to a better understanding of p75NTR and sortilin roles regarding PNS homeostasis and disease.
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Affiliation(s)
- Nádia P. Gonçalves
- Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic-EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; (M.U.); (C.B.V.)
| | - Yan Yan
- Interdisciplinary Nanoscience Centre (iNANO), Aarhus University, 8000 Aarhus, Denmark; (Y.Y.); (M.T.V.); (J.K.)
- Omiics ApS, 8000 Aarhus, Denmark
| | - Maj Ulrichsen
- Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic-EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; (M.U.); (C.B.V.)
| | - Morten T. Venø
- Interdisciplinary Nanoscience Centre (iNANO), Aarhus University, 8000 Aarhus, Denmark; (Y.Y.); (M.T.V.); (J.K.)
- Omiics ApS, 8000 Aarhus, Denmark
| | - Ebbe T. Poulsen
- Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark; (E.T.P.); (J.J.E.)
| | - Jan J. Enghild
- Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark; (E.T.P.); (J.J.E.)
| | - Jørgen Kjems
- Interdisciplinary Nanoscience Centre (iNANO), Aarhus University, 8000 Aarhus, Denmark; (Y.Y.); (M.T.V.); (J.K.)
- Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark; (E.T.P.); (J.J.E.)
| | - Christian B. Vægter
- Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic-EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; (M.U.); (C.B.V.)
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50
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Costa RO, Martins H, Martins LF, Cwetsch AW, Mele M, Pedro JR, Tomé D, Jeon NL, Cancedda L, Jaffrey SR, Almeida RD. Synaptogenesis Stimulates a Proteasome-Mediated Ribosome Reduction in Axons. Cell Rep 2020; 28:864-876.e6. [PMID: 31340150 PMCID: PMC6686882 DOI: 10.1016/j.celrep.2019.06.080] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 12/21/2018] [Accepted: 06/21/2019] [Indexed: 11/19/2022] Open
Abstract
Ribosomes and a subset of cellular mRNAs are trafficked into axons of developing neurons. The axonal localization of translational machinery allows new proteins to be rapidly and locally synthesized during axonal growth and pathfinding. However, in mature neurons, axonal ribosomes are significantly reduced or even absent. The mechanism that elicits this removal is currently unknown. Here, we demonstrate that synapse formation is the trigger for ribosome reduction in mature axons. In vivo analysis shows that axonal ribosome levels decrease in rat brain at a developmental stage coincident with synapse formation. Next, we observe in vitro that different synaptogenic inducers trigger an overall decrease of ribosomal proteins and rRNA in the axons of spinal motor neurons. We further observe that this process is dependent on the ubiquitin-proteasome system but not on autophagy. Together, these data identify synaptogenesis as the long missing biological trigger that leads to ribosome disappearance during axonal maturation. The mechanism behind the striking loss of ribosomes from axons during neuronal maturation is unknown. Using in vivo and in vitro models, including neuron-muscle co-cultures and combining biochemistry and imaging techniques, Costa et al. demonstrate that synapse formation triggers ribosome reduction by a mechanism involving the ubiquitin-proteasome system.
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Affiliation(s)
- Rui O Costa
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal.
| | - Helena Martins
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
| | - Luís F Martins
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal; PhD Programme in Experimental Biology and Biomedicine (PDBEB), Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Andrzej W Cwetsch
- NBT - Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy
| | - Miranda Mele
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
| | - Joana R Pedro
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
| | - Diogo Tomé
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; iBiMED - Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, Aveiro, Portugal
| | - Noo Li Jeon
- Institute of Advanced Machinery and Design, Seoul National University, Seoul, Republic of Korea; Department of Mechanical and Aerospace Engineering, Seoul National University, Seoul, Republic of Korea
| | - Laura Cancedda
- NBT - Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy; Dulbecco Telethon Institute, Roma, Italy
| | - Samie R Jaffrey
- Department of Pharmacology, Weill Medical College of Cornell University, New York, NY 10065, USA
| | - Ramiro D Almeida
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal; iBiMED - Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, Aveiro, Portugal.
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