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Tian X, Yuan M, Li L, Chen D, Liu B, Zou X, He M, Wu Z. Enterovirus 71 Induces Mitophagy via PINK1/Parkin Signaling Pathway to Promote Viral Replication. FASEB J 2025; 39:e70659. [PMID: 40396408 DOI: 10.1096/fj.202403315r] [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: 12/21/2024] [Revised: 04/27/2025] [Accepted: 05/12/2025] [Indexed: 05/22/2025]
Abstract
Enterovirus 71 (EV71) infection poses a global public health challenge, especially in infants and young children, with severe cases leading to fatal consequences. EV71 infection modulates various biological processes of the host and evades host immunity through multiple mechanisms. The balance of mitochondrial dynamics is important for cellular homeostasis. However, the mechanisms underlying EV71-induced cellular damage via mitophagy remain unclear. In the current study, we showed that EV71 infection significantly reduced the total and mitochondrial ATP contents in cells, as well as the expression of mitochondrial proteins TOM20 and TIM23. Then, EV71 infection increased the protein levels of PINK1, Parkin, and LC3B, suggesting that EV71 infection triggers the mitophagy. Silencing PINK1 caused a significant reduction in viral replication, while overexpressing Parkin promoted the replication of EV71. Moreover, CsA treatment, as a mitophagy inhibitor, alleviated pathological damage and suppressed the replication of EV71 in vivo. Mechanistic study showed that silencing PINK1 inhibited the cleavage of MAVS by EV71, while overexpressing Parkin enhanced the cleavage of MAVS by EV71, suggesting that PINK1-mediated mitophagy was involved in regulating innate immunity. Furthermore, we found that EV71 infection promoted the release of mitochondria carrying EV71 virions into the extracellular environment, which mediated infection of other cells, thus facilitating virus spreading. In addition, we also demonstrated that the extracellular mitochondria induced the degradation of MAVS and mitophagy promoted the release of mitochondria in EV71-infected HeLa cells. In conclusion, these findings suggest that EV71 infection induces PINK1-mediated mitophagy, which inhibits innate immunity and facilitates virus replication.
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Affiliation(s)
- Xiaoyan Tian
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, China
| | - Meng Yuan
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, China
| | - Linrun Li
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, China
| | - Deyan Chen
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, China
| | - Bingxin Liu
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, China
| | - Xue Zou
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, China
| | - Miao He
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, China
| | - Zhiwei Wu
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, China
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, China
- State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, China
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Ngana GS, Di Bernardo MA, Surette MG, MacNeil LT. Actinomyces viscosus promotes neuroprotection in C. elegans models of Parkinson's disease. Mech Ageing Dev 2025; 225:112061. [PMID: 40258426 DOI: 10.1016/j.mad.2025.112061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 04/04/2025] [Accepted: 04/11/2025] [Indexed: 04/23/2025]
Abstract
Parkinson's Disease is characterized by selective degeneration of dopaminergic neurons, primarily in the substantia nigra pars compacta, as well as accumulation of alpha-synuclein enriched protein aggregates within neurons. The pathogenesis of PD is still not completely understood, and no treatments exist that alter disease progression. Obvious genetic causes are detected in only a small number of PD patients (5-10 %), suggesting that environmental factors play a significant role the development of PD. Correlative studies suggest that the microbiota could be an important environmental modifier of neurodegeneration. We identified a microbiotal isolate, Actinomyces viscosus, that reduced neurodegeneration in C. elegans expressing a pathological mutant form (G2019S) of leucine-rich repeat kinase 2 (LRRK2) in dopaminergic neurons. A. viscosus also suppressed autophagic dysfunction in these animals and reduced alpha-synuclein aggregation in a synucleinopathy model. Global gene expression analysis revealed increased expression of aspartic cathepsins in response to A. viscosus. Consistent with the involvement of these proteins in neuroprotection, we found that reducing aspartic cathepsin function increased neurodegeneration in the LRRK2 transgenic model. Our findings contribute to the current understanding of how the gut microbiota may influence PD, elucidating one potential mechanism of microbiota-mediated neuroprotection.
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Affiliation(s)
- G Sophie Ngana
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St W., Hamilton, ON, Canada
| | - Mercedes A Di Bernardo
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St W., Hamilton, ON, Canada
| | - Michael G Surette
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St W., Hamilton, ON, Canada; Farncombe Family Digestive Health Research Institute, McMaster University, 1280 Main St W, Hamilton, ON, Canada; Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, 1280 Main St W, Hamilton ON, Canada; Department of Medicine, McMaster University, 1280 Main St W, Hamilton, ON, Canada
| | - Lesley T MacNeil
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St W., Hamilton, ON, Canada; Farncombe Family Digestive Health Research Institute, McMaster University, 1280 Main St W, Hamilton, ON, Canada; Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, 1280 Main St W, Hamilton ON, Canada.
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Levi-D'Ancona E, Walker EM, Zhu J, Deng Y, Sidarala V, Stendahl AM, Reck EC, Henry-Kanarek BA, Lietzke AC, Pasmooij MB, Hubers DL, Basrur V, Ghosh S, Stiles L, Nesvizhskii AI, Shirihai OS, Soleimanpour SA. TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and -independent mitophagy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.31.635900. [PMID: 39974969 PMCID: PMC11838480 DOI: 10.1101/2025.01.31.635900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Activation of innate immune signaling occurs during the progression of immunometabolic diseases, including type 2 diabetes (T2D), yet the impact of innate immune signaling on glucose homeostasis is controversial. Here, we report that the E3 ubiquitin ligase TRAF6 integrates innate immune signals following diet-induced obesity to promote glucose homeostasis through the induction of mitophagy. Whereas TRAF6 was dispensable for glucose homeostasis and pancreatic β-cell function under basal conditions, TRAF6 was pivotal for insulin secretion, mitochondrial respiration, and increases in mitophagy following metabolic stress in both mouse and human islets. Indeed, TRAF6 was critical for the recruitment and function of machinery within both the ubiquitin-mediated (Parkin-dependent) and receptor-mediated (Parkin-independent) mitophagy pathways upon metabolic stress. Intriguingly, the effect of TRAF6 deficiency on glucose homeostasis and mitophagy was fully reversed by concomitant Parkin deficiency. Thus, our results implicate a role for TRAF6 in the cross-regulation of both ubiquitin- and receptor- mediated mitophagy through the restriction of Parkin. Together, we illustrate that β-cells engage innate immune signaling to adaptively respond to a diabetogenic environment.
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Zheng C, Nguyen KK, Vishnivetskiy SA, Gurevich VV, Gurevich EV. Arrestin-3 binds parkin and enhances parkin-dependent mitophagy. J Neurochem 2025; 169:e16043. [PMID: 38196269 PMCID: PMC11231064 DOI: 10.1111/jnc.16043] [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: 05/08/2023] [Revised: 12/12/2023] [Accepted: 12/14/2023] [Indexed: 01/11/2024]
Abstract
Arrestins were discovered for their role in homologous desensitization of G-protein-coupled receptors (GPCRs). Later non-visual arrestins were shown to regulate several signaling pathways. Some of these pathways require arrestin binding to GPCRs, the regulation of others is receptor independent. Here, we demonstrate that arrestin-3 binds the E3 ubiquitin ligase parkin via multiple sites, preferentially interacting with its RING0 domain. Identification of the parkin domains involved suggests that arrestin-3 likely relieves parkin autoinhibition and/or stabilizes the enzymatically active "open" conformation of parkin. Arrestin-3 binding enhances ubiquitination by parkin of the mitochondrial protein mitofusin-1 and facilitates parkin-mediated mitophagy in HeLa cells. Furthermore, arrestin-3 and its mutant with enhanced parkin binding rescue mitofusin-1 ubiquitination and mitophagy in the presence of the Parkinson's disease-associated R275W parkin mutant, which is defective in both functions. Thus, modulation of parkin activity via arrestin-3 might be a novel strategy of anti-parkinsonian therapy.
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Affiliation(s)
- Chen Zheng
- Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA
| | - Kevin K. Nguyen
- Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA
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Lei X, Wu S, Xu Z, Xu Q, Cao H, Zhan Z, Qin Q, Wei J. Parkin is a critical factor in grouper immune response to virus infection. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2025; 162:105293. [PMID: 39608657 DOI: 10.1016/j.dci.2024.105293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 10/15/2024] [Accepted: 11/25/2024] [Indexed: 11/30/2024]
Abstract
Parkin is an E3 ubiquitinated ligase that mainly participates in mitophagy and plays an essential biological role in organisms. To investigate Parkin's function in fish, a Parkin homolog was cloned from Epinephelus coioides (EcParkin). The open reading frame (ORF) of EcParkin consists of 1461 nucleotides and encodes a protein of 486 amino acids, with a predicted molecular weight of 53.32 kDa. EcParkin was highly expressed in the heart, kidney, and head kidney of healthy groupers, especially in the heart. The expression levels of EcParkin were upregulated after Singapore grouper iridovirus (SGIV) and red-spotted grouper nervous necrosis virus (RGNNV) infection. Intracellular localization studies revealed that EcParkin is distributed in both the cytoplasm and nucleus of GS cells. Overexpression of EcParkin promoted SGIV and RGNNV replication in vitro, while knockdown of EcParkin inhibited SGIV and RGNNV replication. EcParkin suppressed the promoter activities of IFN-β, ISRE, and NF-κB, as well as the expression of interferon-related factors and inflammatory cytokines. EcParkin was found to colocalize and interact with EcMDA5, EcMAVS, EcTBK1, EcIRF3, and EcIRF7. Additionally, EcParkin enhanced LC3-II production in GS cells. These findings suggest that EcParkin may play a crucial role in the antiviral innate immunity and cellular autophagy of fish.
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Affiliation(s)
- Xiaoxia Lei
- College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Siting Wu
- College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Zhuqing Xu
- College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Qiongyue Xu
- College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Helong Cao
- College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Zhouling Zhan
- College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Qiwei Qin
- College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China; Nansha-South China Agricultural University Fishery Research Institute, Guangzhou, 511400, China.
| | - Jingguang Wei
- College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China; Nansha-South China Agricultural University Fishery Research Institute, Guangzhou, 511400, China.
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Chauhan H, Carruthers NJ, Stemmer PM, Schneider BL, Moszczynska A. Interactions of VMAT2 with CDCrel-1 and Parkin in Methamphetamine Neurotoxicity. Int J Mol Sci 2024; 25:13070. [PMID: 39684782 DOI: 10.3390/ijms252313070] [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: 08/25/2024] [Revised: 11/05/2024] [Accepted: 11/07/2024] [Indexed: 12/18/2024] Open
Abstract
In recent years, methamphetamine (METH) misuse in the US has been rapidly increasing, and there is no FDA-approved pharmacotherapy for METH use disorder (MUD). In addition to being dependent on the drug, people with MUD develop a variety of neurological problems related to the toxicity of this drug. A variety of molecular mechanisms underlying METH neurotoxicity has been identified, including the dysfunction of the neuroprotective protein parkin. However, it is not known whether parkin loss of function within striatal dopaminergic (DAergic) terminals translates into decreased DA storage capacity. This study examined the relationship between parkin, its substrate cell division cycle related-1 (CDCrel-1) associated with synaptic vesicles, and vesicular monoamine transporter-2 (VMAT2) responsible for packaging DA in an in vivo model of METH neurotoxicity. To assess the individual differences in response to METH's neurotoxic effects, a large group of male Sprague Dawley rats were treated with binge METH or saline and sacrificed 1 h or 24 h later. This study is the first to show that CDCrel-1 interacts with VMAT2 in the rat striatum and that binge METH can alter this interaction as well as the levels and subcellular localization of CDCrel-1. The proteomic analysis of VMAT-2-associated proteins revealed the upregulation of several proteins involved in the exocytosis/endocytosis cycle and responses to stress. The results suggest that DAergic neurons are engaged in counteracting METH-induced toxic effects, including attempts to increase endocytosis and autophagy at 1 h after the METH binge, with the responses varying widely between individual rats. Studying CDCrel-1, VMAT2, and other proteins in large groups of outbred rats can help define individual genetic and molecular differences in responses to METH neurotoxicity, which, in turn, may aid treating humans suffering from MUD and its neurological consequences.
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Affiliation(s)
- Heli Chauhan
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48201, USA
| | - Nicholas J Carruthers
- Institute of Environmental Health Sciences and Proteomics Core Facility, 540 East Canfield Ave., Detroit, MI 48202, USA
- Bioinformatics Core, Michigan Medicine, University of Michigan, NCRC Building 14, 2800 Plymouth Rd., Ann Arbor, MI 48109, USA
| | - Paul M Stemmer
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48201, USA
- Institute of Environmental Health Sciences and Proteomics Core Facility, 540 East Canfield Ave., Detroit, MI 48202, USA
| | - Bernard L Schneider
- Bertarelli Platform for Gene Therapy, École Polytechnique Fédérale de Lausanne, School of Life Sciences, Ch. Des Mines 9, CH-1202 Geneva, Switzerland
| | - Anna Moszczynska
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48201, USA
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Schampera JN, Schwan C. Septin dynamics and organization in mammalian cells. Curr Opin Cell Biol 2024; 91:102442. [PMID: 39509956 DOI: 10.1016/j.ceb.2024.102442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/23/2024] [Accepted: 10/08/2024] [Indexed: 11/15/2024]
Abstract
Septins are involved in many important cellular processes, and septin dysfunction has been implicated in various pathologies, such as cancer. Like other components of the cytoskeleton -F-actin, microtubules, and intermediate filaments-septins can self-assemble into filaments and higher-order structures. These non-polar filaments are assembled from complex and variable multimeric building blocks. Septins exhibit a distinct preference for interacting with actin and microtubule structures, particularly at the interface with cellular membrane. Although they are crucial for many vital cellular functions and are frequently observed at prominent cellular structures like stress fibers, cilia, and neuronal processes, our understanding of the regulation of septin filament dynamics and the organized assembly of higher-order structures remains limited. However, recent insights into the architecture of septin filaments, the structure of crucial septin domains, and their interactions with other cellular components (F-actin, microtubules, membranes) and regulatory proteins may now pave the way for rapid progress.
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Affiliation(s)
- Janik N Schampera
- Institute for Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
| | - Carsten Schwan
- Institute for Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.
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Safreena N, Nair IC, Chandra G. Therapeutic potential of Parkin and its regulation in Parkinson's disease. Biochem Pharmacol 2024; 230:116600. [PMID: 39500382 DOI: 10.1016/j.bcp.2024.116600] [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: 07/25/2024] [Revised: 10/05/2024] [Accepted: 10/28/2024] [Indexed: 11/14/2024]
Abstract
Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the midbrain substantia nigra, resulting in motor and non-motor symptoms. While the exact etiology of PD remains elusive, a growing body of evidence suggests that dysfunction in the parkin protein plays a pivotal role in the pathogenesis of the disease. Parkin is an E3 ubiquitin ligase that ubiquitinates substrate proteins to control a number of crucial cellular processes including protein catabolism, immune response, and cellular apoptosis.While autosomal recessive mutations in the PARK2 gene, which codes for parkin, are linked to an inherited form of early-onset PD, heterozygous mutations in PARK2 have also been reported in the more commonly occurring sporadic PD cases. Impairment of parkin's E3 ligase activity is believed to play a pathogenic role in both familial and sporadic forms of PD.This article provides an overview of the current understanding of the mechanistic basis of parkin's E3 ligase activity, its major physiological role in controlling cellular functions, and how these are disrupted in familial and sporadic PD. The second half of the manuscript explores the currently available and potential therapeutic strategies targeting parkin structure and/or function in order to slow down or mitigate the progressive neurodegeneration in PD.
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Affiliation(s)
- Narukkottil Safreena
- Cell Biology Laboratory, Center for Development and Aging Research, Inter University Center for Biomedical Research & Super Specialty Hospital, Mahatma Gandhi University Campus at Thalappady, Rubber Board PO, Kottayam 686009, Kerala, India
| | - Indu C Nair
- SAS SNDP Yogam College, Konni, Pathanamthitta 689691, Kerala, India
| | - Goutam Chandra
- Cell Biology Laboratory, Center for Development and Aging Research, Inter University Center for Biomedical Research & Super Specialty Hospital, Mahatma Gandhi University Campus at Thalappady, Rubber Board PO, Kottayam 686009, Kerala, India.
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Lal R, Singh A, Watts S, Chopra K. Experimental models of Parkinson's disease: Challenges and Opportunities. Eur J Pharmacol 2024; 980:176819. [PMID: 39029778 DOI: 10.1016/j.ejphar.2024.176819] [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: 09/07/2023] [Revised: 05/29/2024] [Accepted: 07/17/2024] [Indexed: 07/21/2024]
Abstract
Parkinson's disease (PD) is a widespread neurodegenerative disorder occurs due to the degradation of dopaminergic neurons present in the substantia nigra pars compacta (SNpc). Millions of people are affected by this devastating disorder globally, and the frequency of the condition increases with the increase in the elderly population. A significant amount of progress has been made in acquiring more knowledge about the etiology and the pathogenesis of PD over the past decades. Animal models have been regarded to be a vital tool for the exploration of complex molecular mechanisms involved in PD. Various animals used as models for disease monitoring include vertebrates (zebrafish, rats, mice, guinea pigs, rabbits and monkeys) and invertebrate models (Drosophila, Caenorhabditis elegans). The animal models most relevant for study of PD are neurotoxin induction-based models (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-Hydroxydopamine (6-OHDA) and agricultural pesticides (rotenone, paraquat), pharmacological models (reserpine or haloperidol treated rats), genetic models (α-synuclein, Leucine-rich repeat kinase 2 (LRRK2), DJ-1, PINK-1 and Parkin). Several non-mammalian genetic models such as zebrafish, Drosophila and Caenorhabditis elegance have also gained popularity in recent years due to easy genetic manipulation, presence of genes homologous to human PD, and rapid screening of novel therapeutic molecules. In addition, in vitro models (SH-SY5Y, PC12, Lund human mesencephalic (LUHMES) cells, Human induced pluripotent stem cell (iPSC), Neural organoids, organ-on-chip) are also currently in trend providing edge in investigating molecular mechanisms involved in PD as they are derived from PD patients. In this review, we explain the current situation and merits and demerits of the various animal models.
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Affiliation(s)
- Roshan Lal
- Pharmacology Division, University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, 160014, India.
| | - Aditi Singh
- TR(i)P for Health Laboratory, Centre for Excellence in Functional Foods, Department of Food and Nutritional Biotechnology, National Agri-Food Biotechnology Institute (NABI), Knowledge City, Sector 81, SAS Nagar, Punjab, 140306, India.
| | - Shivam Watts
- Pharmacology Division, University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, 160014, India.
| | - Kanwaljit Chopra
- Pharmacology Division, University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, 160014, India.
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Connelly EM, Rintala-Dempsey AC, Gundogdu M, Freeman EA, Koszela J, Aguirre JD, Zhu G, Kämäräinen O, Tadayon R, Walden H, Shaw GS. Capturing the catalytic intermediates of parkin ubiquitination. Proc Natl Acad Sci U S A 2024; 121:e2403114121. [PMID: 39078678 PMCID: PMC11317638 DOI: 10.1073/pnas.2403114121] [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: 02/13/2024] [Accepted: 06/24/2024] [Indexed: 07/31/2024] Open
Abstract
Parkin is an E3 ubiquitin ligase implicated in early-onset forms of Parkinson's disease. It catalyzes a transthiolation reaction by accepting ubiquitin (Ub) from an E2 conjugating enzyme, forming a short-lived thioester intermediate, and transfers Ub to mitochondrial membrane substrates to signal mitophagy. A major impediment to the development of Parkinsonism therapeutics is the lack of structural and mechanistic detail for the essential, short-lived transthiolation intermediate. It is not known how Ub is recognized by the catalytic Rcat domain in parkin that enables Ub transfer from an E2~Ub conjugate to the catalytic site and the structure of the transthiolation complex is undetermined. Here, we capture the catalytic intermediate for the Rcat domain of parkin in complex with ubiquitin (Rcat-Ub) and determine its structure using NMR-based chemical shift perturbation experiments. We show that a previously unidentified α-helical region near the Rcat domain is unmasked as a recognition motif for Ub and guides the C-terminus of Ub toward the parkin catalytic site. Further, we apply a combination of guided AlphaFold modeling, chemical cross-linking, and single turnover assays to establish and validate a model of full-length parkin in complex with UbcH7, its donor Ub, and phosphoubiquitin, trapped in the process of transthiolation. Identification of this catalytic intermediate and orientation of Ub with respect to the Rcat domain provides important structural insights into Ub transfer by this E3 ligase and explains how the previously enigmatic Parkinson's pathogenic mutation T415N alters parkin activity.
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Affiliation(s)
- Elizabeth M. Connelly
- Department of Biochemistry, The University of Western Ontario, London, ONN6A 5C1, Canada
| | | | - Mehmet Gundogdu
- School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, GlasgowG12 8QQ, UK
| | - E. Aisha Freeman
- Department of Biochemistry, The University of Western Ontario, London, ONN6A 5C1, Canada
| | - Joanna Koszela
- School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, GlasgowG12 8QQ, UK
| | - Jacob D. Aguirre
- Department of Biochemistry, The University of Western Ontario, London, ONN6A 5C1, Canada
| | - Grace Zhu
- Department of Biochemistry, The University of Western Ontario, London, ONN6A 5C1, Canada
| | - Outi Kämäräinen
- School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, GlasgowG12 8QQ, UK
| | - Roya Tadayon
- Department of Biochemistry, The University of Western Ontario, London, ONN6A 5C1, Canada
| | - Helen Walden
- School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, GlasgowG12 8QQ, UK
| | - Gary S. Shaw
- Department of Biochemistry, The University of Western Ontario, London, ONN6A 5C1, Canada
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Chauhan H, Carruthers N, Stemmer P, Schneider BP, Moszczynska A. Neurotoxic Methamphetamine Doses Alter CDCel-1 Levels and Its Interaction with Vesicular Monoamine Transporter-2 in Rat Striatum. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.21.604458. [PMID: 39091864 PMCID: PMC11291068 DOI: 10.1101/2024.07.21.604458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/04/2024]
Abstract
In recent years, methamphetamine METH misuse in the US has been rapidly increasing and there is no FDA-approved pharmacotherapy for METH use disorder (MUD). In addition to being dependent on the drug, people with MUD develop a variety of neurological problems related to the toxicity of this drug. A variety of molecular mechanisms underlying METH neurotoxicity has been identified, including dysfunction of the neuroprotective protein parkin. However, it is not known whether parkin loss of function within striatal dopaminergic (DAergic) terminals translates into a decrease in DA storage capacity. This study examined the relationship between parkin, its substrate cell division cycle related-1 (CDCrel-1), and vesicular monoamine transporter-2 (VMAT2) in METH neurotoxicity in male Sprague Dawley rats. To also assess individual differences in response to METH's neurotoxic effects, a large group of rats was treated with binge METH or saline and sacrificed 1h or 24h later. This study is the first to show that binge METH alters the levels and subcellular localization of CDCrel-1 and that CDCrel-1 interacts with VMAT2 and increases its levels at the plasma membrane. Furthermore, we found wide individual differences in the responses of measured indices to METH. Proteomic analysis of VMAT-2-associated proteins revealed upregulation of several proteins involved in the exocytosis/endocytosis cycle. The results suggest that at 1h after METH binge, DAergic neurons are engaged in counteracting METH-induced toxic effects, including oxidative stress- and hyperthermia-induced inhibition of synaptic vesicle cycling, with the responses varying between individual rats. Studying CDCrel-1, VMAT2, and other proteins in large groups of outbred rats can help define individual genetic and molecular differences in responses to METH neurotoxicity which, in turn, will aid treating humans suffering from METH use disorder and its neurological consequences.
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Affiliation(s)
- Heli Chauhan
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave, Detroit, MI, USA 48201
| | - Nick Carruthers
- Institute of Environmental Health Sciences and Proteomics Core Facility, 540 East Canfield Ave., Detroit, MI 48202
| | - Paul Stemmer
- Institute of Environmental Health Sciences and Proteomics Core Facility, 540 East Canfield Ave., Detroit, MI 48202
| | - Bernard P. Schneider
- Brain Mind Institute École Polytechnique Fédérale de Lausanne School of Life Sciences, Ch. Des Mines, 9, CH-1202 Geneve, Switzerland
| | - Anna Moszczynska
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave, Detroit, MI, USA 48201
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Koszela J, Rintala-Dempsey A, Salzano G, Pimenta V, Kamarainen O, Gabrielsen M, Parui AL, Shaw GS, Walden H. A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.03.597144. [PMID: 38895334 PMCID: PMC11185606 DOI: 10.1101/2024.06.03.597144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Mutations in the gene encoding for the E3 ubiquitin ligase Parkin have been linked to early-onset Parkinson's disease. Besides many other cellular roles, Parkin is involved in clearance of damaged mitochondria via mitophagy - a process of particular importance in dopaminergic neurons. Upon mitochondrial damage, Parkin accumulates at the outer mitochondrial membrane and is activated, leading to ubiquitination of many mitochondrial substrates and recruitment of mitophagy effectors. While the activation mechanisms of autoinhibited Parkin have been extensively studied, it remains unknown how Parkin recognises its substrates for ubiquitination, and no substrate interaction site in Parkin has been reported. Here, we identify a conserved region in the flexible linker between the Ubl and RING0 domains of Parkin, which is indispensable for Parkin interaction with the mitochondrial GTPase Miro1. Our results explain the preferential targeting and ubiquitination of Miro1 by Parkin and provide a biochemical explanation for the presence of Parkin at the mitochondrial membrane prior to activation induced by mitochondrial damage. Our findings are important for understanding mitochondrial homeostasis and may inspire new therapeutic avenues for Parkinson's disease.
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Affiliation(s)
- Joanna Koszela
- School of Molecular Biosciences, University of Glasgow, Glasgow, UK
| | - Anne Rintala-Dempsey
- Department of Biochemistry, The University of Western Ontario, London, ON, Canada
| | | | - Viveka Pimenta
- Department of Biochemistry, The University of Western Ontario, London, ON, Canada
| | - Outi Kamarainen
- School of Molecular Biosciences, University of Glasgow, Glasgow, UK
| | - Mads Gabrielsen
- Integrated Protein Analysis, Shared Research Facilities, University of Glasgow, Glasgow, UK
| | - Aasna L Parui
- School of Molecular Biosciences, University of Glasgow, Glasgow, UK
| | - Gary S Shaw
- Department of Biochemistry, The University of Western Ontario, London, ON, Canada
| | - Helen Walden
- School of Molecular Biosciences, University of Glasgow, Glasgow, UK
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13
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Jin X, Si X, Lei X, Liu H, Shao A, Li L. Disruption of Dopamine Homeostasis Associated with Alteration of Proteins in Synaptic Vesicles: A Putative Central Mechanism of Parkinson's Disease Pathogenesis. Aging Dis 2024; 15:1204-1226. [PMID: 37815908 PMCID: PMC11081171 DOI: 10.14336/ad.2023.0821-2] [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: 05/27/2023] [Accepted: 08/21/2023] [Indexed: 10/12/2023] Open
Abstract
Vestigial dopaminergic cells in PD have selectivity for a sub-class of hypersensitive neurons with the nigrostriatal dopamine (DA) tract. DA is modulated in pre-synaptic nerve terminals to remain stable. To be specific, proteins at DA release sites that have a function of synthesizing and packing DA in cytoplasm, modulating release and reingestion, and changing excitability of neurons, display regional discrepancies that uncover relevancy of the observed sensitivity to neurodegenerative changes. Although the reasons of a majority of PD cases are still indistinct, heredity and environment are known to us to make significant influences. For decades, genetic analysis of PD patients with heredity in family have promoted our comprehension of pathogenesis to a great extent, which reveals correlative mechanisms including oxidative stress, abnormal protein homeostasis and mitochondrial dysfunction. In this review, we review the constitution of presynaptic vesicle related to DA homeostasis and describe the genetic and environmental evidence of presynaptic dysfunction that increase risky possibility of PD concerning intracellular vesicle transmission and their functional outcomes. We summarize alterations in synaptic vesicular proteins with great involvement in the reasons of some DA neurons highly vulnerable to neurodegenerative changes. We generalize different potential targets and therapeutic strategies for different pathogenic mechanisms, providing a reference for further studies of PD treatment in the future. But it remains to be further researched on this recently discovered and converging mechanism of vesicular dynamics and PD, which will provide a more profound comprehension and put up with new therapeutic tactics for PD patients.
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Affiliation(s)
- Xuanxiang Jin
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Xiaoli Si
- Department of Neurology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
| | - Xiaoguang Lei
- Department of Neurology, First Affiliated Hospital of Kunming Medical University, the First School of Clinical Medicine, Kunming Medical University, Kunming, China.
| | - Huifang Liu
- Division of Neurology, Department of Medicine, University of Hong Kong, Hong Kong.
| | - Anwen Shao
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Disease, Hangzhou, China.
| | - Lingfei Li
- Department of Neurology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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14
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Luo S, Wang D, Zhang Z. Post-translational modification and mitochondrial function in Parkinson's disease. Front Mol Neurosci 2024; 16:1329554. [PMID: 38273938 PMCID: PMC10808367 DOI: 10.3389/fnmol.2023.1329554] [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: 10/29/2023] [Accepted: 12/21/2023] [Indexed: 01/27/2024] Open
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease with currently no cure. Most PD cases are sporadic, and about 5-10% of PD cases present a monogenic inheritance pattern. Mutations in more than 20 genes are associated with genetic forms of PD. Mitochondrial dysfunction is considered a prominent player in PD pathogenesis. Post-translational modifications (PTMs) allow rapid switching of protein functions and therefore impact various cellular functions including those related to mitochondria. Among the PD-associated genes, Parkin, PINK1, and LRRK2 encode enzymes that directly involved in catalyzing PTM modifications of target proteins, while others like α-synuclein, FBXO7, HTRA2, VPS35, CHCHD2, and DJ-1, undergo substantial PTM modification, subsequently altering mitochondrial functions. Here, we summarize recent findings on major PTMs associated with PD-related proteins, as enzymes or substrates, that are shown to regulate important mitochondrial functions and discuss their involvement in PD pathogenesis. We will further highlight the significance of PTM-regulated mitochondrial functions in understanding PD etiology. Furthermore, we emphasize the potential for developing important biomarkers for PD through extensive research into PTMs.
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Affiliation(s)
- Shishi Luo
- Institute for Future Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- Key Laboratory of Rare Pediatric Diseases, Ministry of Education, Hengyang, Hunan, China
- The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, Hunan, China
| | - Danling Wang
- Institute for Future Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- Key Laboratory of Rare Pediatric Diseases, Ministry of Education, Hengyang, Hunan, China
- The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, Hunan, China
| | - Zhuohua Zhang
- Institute for Future Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- Key Laboratory of Rare Pediatric Diseases, Ministry of Education, Hengyang, Hunan, China
- Institute of Molecular Precision Medicine, Xiangya Hospital, Key Laboratory of Molecular Precision Medicine of Hunan Province and Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China
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15
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Jomova K, Raptova R, Alomar SY, Alwasel SH, Nepovimova E, Kuca K, Valko M. Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging. Arch Toxicol 2023; 97:2499-2574. [PMID: 37597078 PMCID: PMC10475008 DOI: 10.1007/s00204-023-03562-9] [Citation(s) in RCA: 650] [Impact Index Per Article: 325.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Accepted: 07/24/2023] [Indexed: 08/21/2023]
Abstract
A physiological level of oxygen/nitrogen free radicals and non-radical reactive species (collectively known as ROS/RNS) is termed oxidative eustress or "good stress" and is characterized by low to mild levels of oxidants involved in the regulation of various biochemical transformations such as carboxylation, hydroxylation, peroxidation, or modulation of signal transduction pathways such as Nuclear factor-κB (NF-κB), Mitogen-activated protein kinase (MAPK) cascade, phosphoinositide-3-kinase, nuclear factor erythroid 2-related factor 2 (Nrf2) and other processes. Increased levels of ROS/RNS, generated from both endogenous (mitochondria, NADPH oxidases) and/or exogenous sources (radiation, certain drugs, foods, cigarette smoking, pollution) result in a harmful condition termed oxidative stress ("bad stress"). Although it is widely accepted, that many chronic diseases are multifactorial in origin, they share oxidative stress as a common denominator. Here we review the importance of oxidative stress and the mechanisms through which oxidative stress contributes to the pathological states of an organism. Attention is focused on the chemistry of ROS and RNS (e.g. superoxide radical, hydrogen peroxide, hydroxyl radicals, peroxyl radicals, nitric oxide, peroxynitrite), and their role in oxidative damage of DNA, proteins, and membrane lipids. Quantitative and qualitative assessment of oxidative stress biomarkers is also discussed. Oxidative stress contributes to the pathology of cancer, cardiovascular diseases, diabetes, neurological disorders (Alzheimer's and Parkinson's diseases, Down syndrome), psychiatric diseases (depression, schizophrenia, bipolar disorder), renal disease, lung disease (chronic pulmonary obstruction, lung cancer), and aging. The concerted action of antioxidants to ameliorate the harmful effect of oxidative stress is achieved by antioxidant enzymes (Superoxide dismutases-SODs, catalase, glutathione peroxidase-GPx), and small molecular weight antioxidants (vitamins C and E, flavonoids, carotenoids, melatonin, ergothioneine, and others). Perhaps one of the most effective low molecular weight antioxidants is vitamin E, the first line of defense against the peroxidation of lipids. A promising approach appears to be the use of certain antioxidants (e.g. flavonoids), showing weak prooxidant properties that may boost cellular antioxidant systems and thus act as preventive anticancer agents. Redox metal-based enzyme mimetic compounds as potential pharmaceutical interventions and sirtuins as promising therapeutic targets for age-related diseases and anti-aging strategies are discussed.
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Affiliation(s)
- Klaudia Jomova
- Department of Chemistry, Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, Nitra, 949 74, Slovakia
| | - Renata Raptova
- Faculty of Chemical and Food Technology, Slovak University of Technology, Bratislava, 812 37, Slovakia
| | - Suliman Y Alomar
- Zoology Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Saleh H Alwasel
- Zoology Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Eugenie Nepovimova
- Department of Chemistry, Faculty of Sciences, University of Hradec Kralove, 50005, Hradec Kralove, Czech Republic
| | - Kamil Kuca
- Department of Chemistry, Faculty of Sciences, University of Hradec Kralove, 50005, Hradec Kralove, Czech Republic
| | - Marian Valko
- Faculty of Chemical and Food Technology, Slovak University of Technology, Bratislava, 812 37, Slovakia.
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16
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Jung BC, Kim SH, Cho Y, Kim YS. Tumor suppressor Parkin induces p53-mediated cell cycle arrest in human lung and colorectal cancer cells. BMB Rep 2023; 56:557-562. [PMID: 37679297 PMCID: PMC10618076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/11/2023] [Accepted: 08/28/2023] [Indexed: 09/09/2023] Open
Abstract
Dysregulation of the E3 ubiquitin ligase Parkin has been linked to various human cancers, indicating that Parkin is a tumor suppressor protein. However, the mechanisms of action of Parkin remain unclear to date. Thus, we aimed to elucidate the mechanisms of action of Parkin as a tumor suppressor in human lung and colorectal cancer cells. Results showed that Parkin overexpression reduced the viability of A549 human lung cancer cells by inducing G2/M cell cycle arrest. In addition, Parkin caused DNA damage and ATM (Ataxia telangiectasia mutated) activation, which subsequently led to p53 activation. It also induced the p53-mediated upregulation of p21 and downregulation of cyclin B1. Moreover, Parkin suppressed the proliferation of HCT-15 human colorectal cancer cells by a mechanism similar to that in A549 lung cancer cells. Taken together, our results suggest that the tumor-suppressive effects of Parkin on lung and colorectal cancer cells are mediated by DNA damage/p53 activation/cyclin B1 reduction/cell cycle arrest. [BMB Reports 2023; 56(10): 557-562].
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Affiliation(s)
- Byung Chul Jung
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA, Wonju 26460, Korea
- Department of Biomedical Laboratory Science, College of Software and Digital Healthcare Convergence, Yonsei University, Wonju 26493, Korea
| | - Sung Hoon Kim
- Department of Biomedical Laboratory Science, College of Software and Digital Healthcare Convergence, Yonsei University, Wonju 26493, Korea
- Department of Biomedical Laboratory Science, Korea Nazarene University, Cheonan 31172, Korea
| | - Yoonjung Cho
- Department of Biomedical Laboratory Science, College of Software and Digital Healthcare Convergence, Yonsei University, Wonju 26493, Korea
- Forensic DNA Division, National Forensic Service, Wonju 26460, Korea
| | - Yoon Suk Kim
- Department of Biomedical Laboratory Science, College of Software and Digital Healthcare Convergence, Yonsei University, Wonju 26493, Korea
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17
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Bolinger AA, Frazier A, La JH, Allen JA, Zhou J. Orphan G Protein-Coupled Receptor GPR37 as an Emerging Therapeutic Target. ACS Chem Neurosci 2023; 14:3318-3334. [PMID: 37676000 PMCID: PMC11144446 DOI: 10.1021/acschemneuro.3c00479] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/08/2023] Open
Abstract
G protein-coupled receptors (GPCRs) are successful druggable targets, making up around 35% of all FDA-approved medications. However, a large number of receptors remain orphaned, with no known endogenous ligand, representing a challenging but untapped area to discover new therapeutic targets. Among orphan GPCRs (oGPCRs) of interest, G protein-coupled receptor 37 (GPR37) is highly expressed in the central nervous system (CNS), particularly in the spinal cord and oligodendrocytes. While its cellular signaling mechanisms and endogenous receptor ligands remain elusive, GPR37 has been implicated in several important neurological conditions, including Parkinson's disease (PD), inflammation, pain, autism, and brain tumors. GPR37 structure, signaling, emerging physiology, and pharmacology are reviewed while integrating a discussion on potential therapeutic indications and opportunities.
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Affiliation(s)
- Andrew A. Bolinger
- Department of Pharmacology and Toxicology, Center for Addiction Sciences and Therapeutics, University of Texas Medical Branch, Galveston, Texas 77555, United States
| | - Andrew Frazier
- Department of Pharmacology and Toxicology, Center for Addiction Sciences and Therapeutics, University of Texas Medical Branch, Galveston, Texas 77555, United States
| | - Jun-Ho La
- Department of Neurobiology, University of Texas Medical Branch, Galveston, Texas 77555, United States
| | - John A. Allen
- Department of Pharmacology and Toxicology, Center for Addiction Sciences and Therapeutics, University of Texas Medical Branch, Galveston, Texas 77555, United States
| | - Jia Zhou
- Department of Pharmacology and Toxicology, Center for Addiction Sciences and Therapeutics, University of Texas Medical Branch, Galveston, Texas 77555, United States
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18
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Sharma K, Menon MB. Decoding post-translational modifications of mammalian septins. Cytoskeleton (Hoboken) 2023; 80:169-181. [PMID: 36797225 DOI: 10.1002/cm.21747] [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: 11/19/2022] [Revised: 01/21/2023] [Accepted: 02/10/2023] [Indexed: 02/18/2023]
Abstract
Septins are cytoskeletal GTPases that form nonpolar filaments and higher-ordered structures and they take part in a wide range of cellular processes. Septins are conserved from yeast to mammals but absent from higher plants. The number of septin genes vary between organisms and they usually form complex heteropolymeric networks. Most septins are known to be capable of GTP hydrolysis which may regulate septin dynamics. Knowledge on regulation of septin function by post-translational modifications is still in its infancy. In this review article, we highlight the post-translational modifications reported for the 13 human septins and discuss their implications on septin functions. In addition to the functionally investigated modifications, we also try to make sense of the complex septin post-translational modification code revealed from large-scale phospho-proteomic datasets. Future studies may determine how these isoform-specific and homology group specific modifications affect septin structure and function.
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Affiliation(s)
- Khushboo Sharma
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi, India
| | - Manoj B Menon
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi, India
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19
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Werner B, Yadav S. Phosphoregulation of the septin cytoskeleton in neuronal development and disease. Cytoskeleton (Hoboken) 2023; 80:275-289. [PMID: 36127729 PMCID: PMC10025170 DOI: 10.1002/cm.21728] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 08/13/2022] [Accepted: 09/12/2022] [Indexed: 11/06/2022]
Abstract
Septins are highly conserved GTP-binding proteins that oligomerize and form higher order structures. The septin cytoskeleton plays an important role in cellular organization, intracellular transport, and cytokinesis. Kinase-mediated phosphorylation of septins regulates various aspects of their function, localization, and dynamics. Septins are enriched in the mammalian nervous system where they contribute to neurodevelopment and neuronal function. Emerging research has implicated aberrant changes in septin cytoskeleton in several human diseases. The mechanisms through which aberrant phosphorylation by kinases contributes to septin dysfunction in neurological disorders are poorly understood and represent an important question for future research with therapeutic implications. This review summarizes the current state of knowledge of the diversity of kinases that interact with and phosphorylate mammalian septins, delineates how phosphoregulation impacts septin dynamics, and describes how aberrant septin phosphorylation contributes to neurological disorders.
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Affiliation(s)
- Bailey Werner
- Department of Pharmacology, University of Washington, Seattle, WA, United States
| | - Smita Yadav
- Department of Pharmacology, University of Washington, Seattle, WA, United States
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20
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Wu A, Zhang W, Zhang G, Ding X, Kang L, Zhou T, Ji M, Guan H. Age-related cataract: GSTP1 ubiquitination and degradation by Parkin inhibits its anti-apoptosis in lens epithelial cells. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2023; 1870:119450. [PMID: 36871745 DOI: 10.1016/j.bbamcr.2023.119450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 02/14/2023] [Accepted: 02/23/2023] [Indexed: 03/07/2023]
Abstract
PURPOSE Oxidative stress-induced apoptosis of lens epithelial cells (LECs) contributes to the pathogenesis of age-related cataract (ARC). The purpose of this research is to underlie the potential mechanism of E3 ligase Parkin and its oxidative stress-associated substrate in cataractogenesis. METHODS The central anterior capsules were obtained from patients with ARC, Emory mice, and corresponding controls. SRA01/04 cells were exposed to H2O2 combined with cycloheximide (a translational inhibitor), MG-132 (a proteasome inhibitor), chloroquine (an autophagy inhibitor), Mdivi-1 (a mitochondrial division inhibitor), respectively. Co-immunoprecipitation was employed to detect protein-protein interactions and ubiquitin-tagged protein products. Levels of proteins and mRNA were evaluated by western blotting and quantitative RT-PCR assays. RESULTS Glutathione-S-transferase P1 (GSTP1) was identified as a novel Parkin substrate. Compared with corresponding controls, GSTP1 was significantly decreased in the anterior lens capsules obtained from human cataracts and Emory mice. Similarly, GSTP1 was declined in H2O2-stimulated SRA01/04 cells. Ectopic expression of GSTP1 mitigated H2O2-induced apoptosis, whereas silencing GSTP1 aggregated apoptosis. In addition, H2O2 stimulation and Parkin overexpression could promote the degradation of GSTP1 through the ubiquitin-proteasome system, autophagy-lysosome pathway, and mitophagy. After co-transfection with Parkin, the non-ubiquitinatable GSTP1 mutant maintained its anti-apoptotic function, while wildtype GSTP1 failed. Mechanistically, GSTP1 might promote mitochondrial fusion through upregulating Mitofusins 1/2 (MFN1/2). CONCLUSION Oxidative stress induces LECs apoptosis via Parkin-regulated degradation of GSTP1, which may provide potential targets for ARC therapy.
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Affiliation(s)
- Anran Wu
- Eye Institute, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu, China
| | - Wenyi Zhang
- Eye Institute, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu, China
| | - Guowei Zhang
- Eye Institute, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu, China
| | - Xuemeng Ding
- Eye Institute, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu, China
| | - Lihua Kang
- Eye Institute, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu, China
| | - Tianqiu Zhou
- Eye Institute, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu, China
| | - Min Ji
- Eye Institute, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu, China.
| | - Huaijin Guan
- Eye Institute, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu, China.
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21
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Nitta Y, Sugie A. Studies of neurodegenerative diseases using Drosophila and the development of novel approaches for their analysis. Fly (Austin) 2022; 16:275-298. [PMID: 35765969 PMCID: PMC9336468 DOI: 10.1080/19336934.2022.2087484] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 05/31/2022] [Accepted: 06/03/2022] [Indexed: 02/09/2023] Open
Abstract
The use of Drosophila in neurodegenerative disease research has contributed to the identification of modifier genes for the pathology. The basis for neurodegenerative disease occurrence in Drosophila is the conservation of genes across species and the ability to perform rapid genetic analysis using a compact brain. Genetic findings previously discovered in Drosophila can reveal molecular pathologies involved in human neurological diseases in later years. Disease models using Drosophila began to be generated during the development of genetic engineering. In recent years, results of reverse translational research using Drosophila have been reported. In this review, we discuss research on neurodegenerative diseases; moreover, we introduce various methods for quantifying neurodegeneration in Drosophila.
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Affiliation(s)
- Yohei Nitta
- Brain Research Institute, Niigata University, Niigata, Japan
| | - Atsushi Sugie
- Brain Research Institute, Niigata University, Niigata, Japan
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22
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Wal P, Dwivedi J, Wal A, Vig H, Singh Y. Detailed insight into the pathophysiology and the behavioral complications associated with the Parkinson's disease and its medications. FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2022. [DOI: 10.1186/s43094-022-00425-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
The loss of dopamine neurons in the substantia nigra, as well as other mostly catecholaminergic neurons, causes many of the motor symptoms that define Parkinson's disease. Parkinson's disease is commonly thought of as a movement disorder, the significant prevalence of psychiatric complications such as cognitive impairment, and psychosis suggests it should be considered a neuropsychiatric illness, and all behavioral complications are linked to growing disability and the medication.
Main body
Apart from the disease-induced abnormalities, there are several other side effects of the disease and also from the medication used to prevent the disease. This article focuses on the pathogenesis of Parkinson’s disease and also the behavioral abnormalities caused by the disease and its medication. The study's data were gathered by searching several review articles and research papers from a variety of sources, including Elsevier, PubMed, Research Gate, Journal of Pharmaceutical Science, etc., from the year 1985 to 2021. Parkinson's disease is a neurodegenerative disease caused by a variety of complex processes. It is responsible not just for motor symptoms, but also for a variety of behavioral symptoms that can arise as a result of the disease and/or medication.
Conclusion
Only symptomatic drugs are available; thus, finding treatments that directly address the disease mechanisms causing Parkinson’s disease is essential. To alleviate the disease's burden on patients and their families, better treatments for the neuropsychiatric repercussions of Parkinson's disease are required.
Graphical Abstract
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23
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Rahman MU, Bilal M, Shah JA, Kaushik A, Teissedre PL, Kujawska M. CRISPR-Cas9-Based Technology and Its Relevance to Gene Editing in Parkinson's Disease. Pharmaceutics 2022; 14:1252. [PMID: 35745824 PMCID: PMC9229276 DOI: 10.3390/pharmaceutics14061252] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 06/07/2022] [Accepted: 06/09/2022] [Indexed: 12/12/2022] Open
Abstract
Parkinson's disease (PD) and other chronic and debilitating neurodegenerative diseases (NDs) impose a substantial medical, emotional, and financial burden on individuals and society. The origin of PD is unknown due to a complex combination of hereditary and environmental risk factors. However, over the last several decades, a significant amount of available data from clinical and experimental studies has implicated neuroinflammation, oxidative stress, dysregulated protein degradation, and mitochondrial dysfunction as the primary causes of PD neurodegeneration. The new gene-editing techniques hold great promise for research and therapy of NDs, such as PD, for which there are currently no effective disease-modifying treatments. As a result, gene therapy may offer new treatment options, transforming our ability to treat this disease. We present a detailed overview of novel gene-editing delivery vehicles, which is essential for their successful implementation in both cutting-edge research and prospective therapeutics. Moreover, we review the most recent advancements in CRISPR-based applications and gene therapies for a better understanding of treating PD. We explore the benefits and drawbacks of using them for a range of gene-editing applications in the brain, emphasizing some fascinating possibilities.
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Affiliation(s)
- Mujeeb ur Rahman
- Department of Toxicology, Faculty of Pharmacy, Poznan University of Medical Sciences, Dojazd 30, 60-631 Poznan, Poland;
| | - Muhammad Bilal
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China;
| | - Junaid Ali Shah
- College of Life Sciences, Jilin University, Changchun 130012, China;
- Fergana Medical Institute of Public Health Uzbekistan, Fergana 150110, Uzbekistan
| | - Ajeet Kaushik
- NanoBioTech Laboratory, Health System Engineering, Department of Environmental Engineering, Florida Polytechnic University, Lakeland, FL 33805, USA;
- School of Engineering, University of Petroleum and Energy Studies (UPES), Dehradun 248007, Uttarakhand, India
| | - Pierre-Louis Teissedre
- Institut des Sciences de la Vigne et du Vin, Université de Bordeaux, EA 4577, Œnologie, 210 Chemin de Leysotte, F-33140 Villenave d’Ornon, France;
- Institut des Sciences de la Vigne et du Vin, INRA, USC 1366 INRA, IPB, 210 Chemin de Leysotte, F-33140 Villenave d’Ornon, France
| | - Małgorzata Kujawska
- Department of Toxicology, Faculty of Pharmacy, Poznan University of Medical Sciences, Dojazd 30, 60-631 Poznan, Poland;
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24
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Liu TW, Chen CM, Chang KH. Biomarker of Neuroinflammation in Parkinson's Disease. Int J Mol Sci 2022; 23:ijms23084148. [PMID: 35456966 PMCID: PMC9028544 DOI: 10.3390/ijms23084148] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 04/02/2022] [Accepted: 04/05/2022] [Indexed: 02/04/2023] Open
Abstract
Parkinson's disease (PD) is caused by abnormal accumulation of α-synuclein in dopaminergic neurons of the substantia nigra, which subsequently causes motor symptoms. Neuroinflammation plays a vital role in the pathogenesis of neurodegeneration in PD. This neuroinflammatory neurodegeneration involves the activation of microglia, upregulation of proinflammatory factors, and gut microbiota. In this review, we summarized the recent findings on detection of PD by using inflammatory biomarkers, such as interleukin (IL)-1β, IL-2, IL-6, IL-10, tumor necrosis factor (TNF)-α; regulated upon activation, normal T cell expressed and presumably secreted (RANTES) and high-sensitivity c-reactive protein (hsCRP); and radiotracers such as [11C]PK11195 and [18F]-FEPPA, as well as by monitoring disease progression and the treatment response. Many PD-causing mutations in SNCA, LRRK2, PRKN, PINK1, and DJ-1 are also associated with neuroinflammation. Several anti-inflammatory medications, including nonsteroidal anti-inflammatory drugs (NSAID), inhibitors of TNF-α and NLR family pyrin domain containing 3 (NLRP3), agonists of nuclear factor erythroid 2-related factor 2 (NRF2), peroxisome proliferator-activated receptor gamma (PPAR-γ), and steroids, have demonstrated neuroprotective effects in in vivo or in vitro PD models. Clinical trials applying objective biomarkers are required to investigate the therapeutic potential of anti-inflammatory medications for PD.
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Affiliation(s)
- Tsai-Wei Liu
- Linkou Medical Center, Department of Neurology, Chang Gung Memorial Hospital, Tauoyan 333, Taiwan; (T.-W.L.); (C.-M.C.)
| | - Chiung-Mei Chen
- Linkou Medical Center, Department of Neurology, Chang Gung Memorial Hospital, Tauoyan 333, Taiwan; (T.-W.L.); (C.-M.C.)
- School of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Kuo-Hsuan Chang
- Linkou Medical Center, Department of Neurology, Chang Gung Memorial Hospital, Tauoyan 333, Taiwan; (T.-W.L.); (C.-M.C.)
- School of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Correspondence: ; Tel.: +886-3-3281200 (ext. 8729); Fax: +886-3-3288849
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Jiang XJ, Wu YQ, Ma R, Chang YM, Li LL, Zhu JH, Liu GP, Li G. PINK1 Alleviates Cognitive Impairments via Attenuating Pathological Tau Aggregation in a Mouse Model of Tauopathy. Front Cell Dev Biol 2022; 9:736267. [PMID: 35059394 PMCID: PMC8763800 DOI: 10.3389/fcell.2021.736267] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 11/25/2021] [Indexed: 01/18/2023] Open
Abstract
As a primary cause of dementia and death in older people, Alzheimer’s disease (AD) has become a common problem and challenge worldwide. Abnormal accumulation of tau proteins in the brain is a hallmark pathology of AD and is closely related to the clinical progression and severity of cognitive deficits. Here, we found that overexpression of phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) effectively promoted the degradation of tau, thereby rescuing neuron loss, synaptic damage, and cognitive impairments in a mouse model of tauopathy with AAV-full-length human Tau (hTau) injected into the hippocampal CA1 area (hTau mice). Overexpression of PINK1 activated autophagy, and chloroquine but not MG132 reversed the PINK1-induced decrease in human Tau levels and cognitive improvement in hTau mice. Furthermore, PINK1 also ameliorated mitochondrial dysfunction induced by hTau. Taken together, our data revealed that PINK1 overexpression promoted degradation of abnormal accumulated tau via the autophagy–lysosome pathway, indicating that PINK1 may be a potential target for AD treatment.
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Affiliation(s)
- Xing Jun Jiang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Qing Wu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rong Ma
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Min Chang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lu Lu Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Hui Zhu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gong Ping Liu
- Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Gang Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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26
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Siddique Y. Neurodegenerative Disorders and the Current State, Pathophysiology, and Management of Parkinson's Disease. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2022; 21:574-595. [PMID: 34477534 DOI: 10.2174/1871527320666210903101841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 12/14/2020] [Accepted: 02/13/2021] [Indexed: 06/13/2023]
Abstract
In the last few decades, major knowledge has been gained about pathophysiological aspects and molecular pathways behind Parkinson's Disease (PD). Based on neurotoxicological studies and postmortem investigations, there is a general concept of how environmental toxicants (neurotoxins, pesticides, insecticides) and genetic factors (genetic mutations in PD-associated proteins) cause depletion of dopamine from substantia nigra pars compacta region of the midbrain and modulate cellular processes leading to the pathogenesis of PD. α-Synuclein, a neuronal protein accumulation in oligomeric form, called protofibrils, is associated with cellular dysfunction and neuronal death, thus possibly contributing to PD propagation. With advances made in identifying loci that contribute to PD, molecular pathways involved in disease pathogenesis are now clear, and introducing therapeutic strategy at the right time may delay the progression. Biomarkers for PD have helped monitor PD progression; therefore, personalized therapeutic strategies can be facilitated. In order to further improve PD diagnostic and prognostic accuracy, independent validation of biomarkers is required.
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Affiliation(s)
- Yasir Siddique
- Drosophila Transgenic Laboratory, Section of Genetics, Department of Zoology, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, 202002, Uttar Pradesh, India
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27
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Giesert F. c-Abl phosphorylation primes PARIS for neurodegeneration. Brain 2021; 144:3555-3557. [PMID: 34788407 DOI: 10.1093/brain/awab412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 10/26/2021] [Indexed: 11/13/2022] Open
Abstract
This scientific commentary refers to ‘Parkin interacting substrate phosphorylation by c-Abl drives dopaminergic neurodegeneration’ by Kim et al. (doi:10.1093/brain/awab356).
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Affiliation(s)
- Florian Giesert
- Institute of Developmental Genetics, Helmholtz Center Munich, Neuherberg, Germany
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28
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Diao RY, Gustafsson AB. Mitochondrial Quality Surveillance: Mitophagy in cardiovascular health and disease. Am J Physiol Cell Physiol 2021; 322:C218-C230. [PMID: 34965154 PMCID: PMC8816617 DOI: 10.1152/ajpcell.00360.2021] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Selective autophagy of mitochondria, known as mitophagy, is a major quality control pathway in the heart that is involved in removing unwanted or dysfunctional mitochondria from the cell. Baseline mitophagy is critical for maintaining fitness of the mitochondrial network by continuous turnover of aged and less-functional mitochondria. Mitophagy is also critical in adapting to stress associated with mitochondrial damage or dysfunction. The removal of damaged mitochondria prevents reactive oxygen species-mediated damage to proteins and DNA and suppresses activation of inflammation and cell death. Impairments in mitophagy are associated with the pathogenesis of many diseases, including cancers, inflammatory diseases, neurodegeneration, and cardiovascular disease. Mitophagy is a highly regulated and complex process that requires the coordination of labeling dysfunctional mitochondria for degradation while simultaneously promoting de novo autophagosome biogenesis adjacent to the cargo. In this review, we provide an update on our current understanding of these steps in mitophagy induction and discuss the physiological and pathophysiological consequences of altered mitophagy in the heart.
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Affiliation(s)
- Rachel Y Diao
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States
| | - Asa B Gustafsson
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States
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29
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Cavini IA, Leonardo DA, Rosa HVD, Castro DKSV, D'Muniz Pereira H, Valadares NF, Araujo APU, Garratt RC. The Structural Biology of Septins and Their Filaments: An Update. Front Cell Dev Biol 2021; 9:765085. [PMID: 34869357 PMCID: PMC8640212 DOI: 10.3389/fcell.2021.765085] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 10/27/2021] [Indexed: 01/22/2023] Open
Abstract
In order to fully understand any complex biochemical system from a mechanistic point of view, it is necessary to have access to the three-dimensional structures of the molecular components involved. Septins and their oligomers, filaments and higher-order complexes are no exception. Indeed, the spontaneous recruitment of different septin monomers to specific positions along a filament represents a fascinating example of subtle molecular recognition. Over the last few years, the amount of structural information available about these important cytoskeletal proteins has increased dramatically. This has allowed for a more detailed description of their individual domains and the different interfaces formed between them, which are the basis for stabilizing higher-order structures such as hexamers, octamers and fully formed filaments. The flexibility of these structures and the plasticity of the individual interfaces have also begun to be understood. Furthermore, recently, light has been shed on how filaments may bundle into higher-order structures by the formation of antiparallel coiled coils involving the C-terminal domains. Nevertheless, even with these advances, there is still some way to go before we fully understand how the structure and dynamics of septin assemblies are related to their physiological roles, including their interactions with biological membranes and other cytoskeletal components. In this review, we aim to bring together the various strands of structural evidence currently available into a more coherent picture. Although it would be an exaggeration to say that this is complete, recent progress seems to suggest that headway is being made in that direction.
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Affiliation(s)
- Italo A Cavini
- São Carlos Institute of Physics, University of São Paulo, São Carlos, Brazil
| | - Diego A Leonardo
- São Carlos Institute of Physics, University of São Paulo, São Carlos, Brazil
| | - Higor V D Rosa
- São Carlos Institute of Physics, University of São Paulo, São Carlos, Brazil
| | - Danielle K S V Castro
- São Carlos Institute of Physics, University of São Paulo, São Carlos, Brazil.,São Carlos Institute of Chemistry, University of São Paulo, São Carlos, Brazil
| | | | | | - Ana P U Araujo
- São Carlos Institute of Physics, University of São Paulo, São Carlos, Brazil
| | - Richard C Garratt
- São Carlos Institute of Physics, University of São Paulo, São Carlos, Brazil
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30
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All Roads Lead to Rome: Different Molecular Players Converge to Common Toxic Pathways in Neurodegeneration. Cells 2021; 10:cells10092438. [PMID: 34572087 PMCID: PMC8468417 DOI: 10.3390/cells10092438] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/12/2021] [Accepted: 09/14/2021] [Indexed: 12/14/2022] Open
Abstract
Multiple neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD) are being suggested to have common cellular and molecular pathological mechanisms, characterized mainly by protein misfolding and aggregation. These large inclusions, most likely, represent an end stage of a molecular cascade; however, the soluble misfolded proteins, which take part in earlier steps of this cascade, are the more toxic players. These pathological proteins, which characterize each specific disease, lead to the selective vulnerability of different neurons, likely resulting from a combination of different intracellular mechanisms, including mitochondrial dysfunction, ER stress, proteasome inhibition, excitotoxicity, oxidative damage, defects in nucleocytoplasmic transport, defective axonal transport and neuroinflammation. Damage within these neurons is enhanced by damage from the nonneuronal cells, via inflammatory processes that accelerate the progression of these diseases. In this review, while acknowledging the hallmark proteins which characterize the most common NDDs; we place specific focus on the common overlapping mechanisms leading to disease pathology despite these different molecular players and discuss how this convergence may occur, with the ultimate hope that therapies effective in one disease may successfully translate to another.
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31
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Day JO, Mullin S. The Genetics of Parkinson's Disease and Implications for Clinical Practice. Genes (Basel) 2021; 12:genes12071006. [PMID: 34208795 PMCID: PMC8304082 DOI: 10.3390/genes12071006] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/21/2021] [Accepted: 06/28/2021] [Indexed: 12/17/2022] Open
Abstract
The genetic landscape of Parkinson’s disease (PD) is characterised by rare high penetrance pathogenic variants causing familial disease, genetic risk factor variants driving PD risk in a significant minority in PD cases and high frequency, low penetrance variants, which contribute a small increase of the risk of developing sporadic PD. This knowledge has the potential to have a major impact in the clinical care of people with PD. We summarise these genetic influences and discuss the implications for therapeutics and clinical trial design.
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Affiliation(s)
- Jacob Oliver Day
- Faculty of Health, University of Plymouth, Plymouth PL4 8AA, UK;
| | - Stephen Mullin
- Faculty of Health, University of Plymouth, Plymouth PL4 8AA, UK;
- Department of Clinical and Movement Neurosciences, University College London Institute of Neurology, London WC1N 3BG, UK
- Correspondence:
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32
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Historical perspective and progress on protein ubiquitination at glutamatergic synapses. Neuropharmacology 2021; 196:108690. [PMID: 34197891 DOI: 10.1016/j.neuropharm.2021.108690] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 06/07/2021] [Accepted: 06/22/2021] [Indexed: 12/23/2022]
Abstract
Transcription-translation coupling leads to the production of proteins that are key for controlling essential neuronal processes that include neuronal development and changes in synaptic strength. Although these events have been a prevailing theme in neuroscience, the regulation of proteins via posttranslational signaling pathways are equally relevant for these neuronal processes. Ubiquitin is one type of posttranslational modification that covalently attaches to its targets/substrates. Ubiquitination of proteins play a key role in multiple signaling pathways, the predominant being removal of its substrates by a large molecular machine called the proteasome. Here, I review 40 years of progress on ubiquitination in the nervous system at glutamatergic synapses focusing on axon pathfinding, synapse formation, presynaptic release, dendritic spine formation, and regulation of postsynaptic glutamate receptors. Finally, I elucidate emerging themes in ubiquitin biology that may challenge our current understanding of ubiquitin signaling in the nervous system.
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33
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Sakuwa M, Adachi T, Yoshida K, Adachi Y, Nakano T, Hanajima R. An autopsy case of PARK2 due to a homozygous exon 2 deletion of parkin and associated with α-synucleinopathy. Neuropathology 2021; 41:293-300. [PMID: 34121225 DOI: 10.1111/neup.12735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 01/20/2021] [Accepted: 01/30/2021] [Indexed: 11/29/2022]
Abstract
Lewy bodies (LBs) are usually detected in patients with idiopathic Parkinson's disease (PD), but there have been few reports of LBs in a familial form of early-onset PD associated with several mutations in parkin, a gene that encodes a ubiquitin E3 ligase involved in mitochondrial homeostasis, being also known as PARK2. Here, we report a case of PD with a PARK2 mutation characterized by a homozygous deletion of exon 2 and incidental LB pathology. A 60-year-old man developed tremor in the upper limbs. Although levodopa was initially effective, his symptoms slowly progressed. His cardiac uptake of 123 I-metaiodobenzylguanidine, as assessed by myocardial scintigraphy, decreased from an early stage after the onset. At the age of 81 years, he developed Legionella pneumonia and died of respiratory failure. Histopathological examination revealed a moderate loss of pigmented neurons, as well as gliosis in the substantia nigra and the locus coeruleus. Little LB-related pathology was found in the locus coeruleus, dorsal nucleus of vagal nerve, and basal nucleus of Meynert. The cardiac sympathetic nerve in the epicardium showed a reduction in the numbers of fibers immunoreactive for tyrosine hydroxylase and phosphorylated neurofilament protein. Genetic analysis of frozen brain materials revealed a homozygous deletion of exon 2 of parkin. To our knowledge, this is the first autopsy case with a homozygous deletion of exon 2 of parkin. The number of LBs was small, the age of disease onset was later than that in typical PARK2-associated PD patients, and cardiac sympathetic denervation was also present. Thus, we considered the LBs in our case as incidental and preclinical α-synucleinopathy.
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Affiliation(s)
- Mayuko Sakuwa
- Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan
| | - Tadashi Adachi
- Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan.,Division of Neuropathology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan
| | - Kentaro Yoshida
- Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan
| | - Yoshiki Adachi
- Department of Neurology, National Hospital Organization Matsue Medical Center, Matsue, Japan
| | - Toshiya Nakano
- Department of Neurology, National Hospital Organization Matsue Medical Center, Matsue, Japan
| | - Ritsuko Hanajima
- Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan
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34
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Murillo-González FE, García-Aguilar R, Vega L, Elizondo G. Regulation of Parkin expression as the key balance between neural survival and cancer cell death. Biochem Pharmacol 2021; 190:114650. [PMID: 34111426 DOI: 10.1016/j.bcp.2021.114650] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 06/02/2021] [Accepted: 06/04/2021] [Indexed: 11/25/2022]
Abstract
Parkin is a cytosolic E3 ubiquitin ligase that plays an important role in neuroprotection by targeting several proteins to be degraded by the 26S proteasome. Its dysfunction has been associated not only with Parkinson's disease (PD) but also with other neurodegenerative pathologies, such as Alzheimer's disease and Huntington's disease. More recently, Parkin has been identified as a tumor suppressor gene implicated in cancer development. Due to the important roles that this E3 ubiquitin ligase plays in cellular homeostasis, its expression, activity, and turnover are tightly regulated. Several reviews have addressed Parkin regulation; however, genetic and epigenetic regulation have been excluded. In addition to posttranslational modifications (PTMs), this review examines the regulatory mechanisms that control Parkin function through gene expression, epigenetic regulation, and degradation. Furthermore, the consequences of disrupting these regulatory processes on human health are discussed.
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Affiliation(s)
| | | | - Libia Vega
- Department of Toxicology, CINVESTAV-IPN, Av. IPN 2508, C.P. 07360 Mexico City, Mexico
| | - Guillermo Elizondo
- Department of Cellular Biology, CINVESTAV-IPN, Av. IPN 2508, C.P. 07360 Mexico City, Mexico.
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35
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Kawabe H, Stegmüller J. The role of E3 ubiquitin ligases in synapse function in the healthy and diseased brain. Mol Cell Neurosci 2021; 112:103602. [DOI: 10.1016/j.mcn.2021.103602] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 01/06/2021] [Accepted: 02/02/2021] [Indexed: 02/08/2023] Open
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36
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Pinto MJ, Tomé D, Almeida RD. The Ubiquitinated Axon: Local Control of Axon Development and Function by Ubiquitin. J Neurosci 2021; 41:2796-2813. [PMID: 33789876 PMCID: PMC8018891 DOI: 10.1523/jneurosci.2251-20.2021] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 01/15/2021] [Accepted: 01/22/2021] [Indexed: 02/01/2023] Open
Abstract
Ubiquitin tagging sets protein fate. With a wide range of possible patterns and reversibility, ubiquitination can assume many shapes to meet specific demands of a particular cell across time and space. In neurons, unique cells with functionally distinct axons and dendrites harboring dynamic synapses, the ubiquitin code is exploited at the height of its power. Indeed, wide expression of ubiquitination and proteasome machinery at synapses, a diverse brain ubiquitome, and the existence of ubiquitin-related neurodevelopmental diseases support a fundamental role of ubiquitin signaling in the developing and mature brain. While special attention has been given to dendritic ubiquitin-dependent control, how axonal biology is governed by this small but versatile molecule has been considerably less discussed. Herein, we set out to explore the ubiquitin-mediated spatiotemporal control of an axon's lifetime: from its differentiation and growth through presynaptic formation, function, and pruning.
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Affiliation(s)
- Maria J Pinto
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, 3004-504, Portugal
| | - Diogo Tomé
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, 3004-504, Portugal
- Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, Aveiro, 3810-193, Portugal
| | - Ramiro D Almeida
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, 3004-504, Portugal
- Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, Aveiro, 3810-193, Portugal
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Radzinski M, Oppenheim T, Metanis N, Reichmann D. The Cys Sense: Thiol Redox Switches Mediate Life Cycles of Cellular Proteins. Biomolecules 2021; 11:469. [PMID: 33809923 PMCID: PMC8004198 DOI: 10.3390/biom11030469] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 03/15/2021] [Accepted: 03/16/2021] [Indexed: 12/14/2022] Open
Abstract
Protein homeostasis is an essential component of proper cellular function; however, sustaining protein health is a challenging task, especially during the aerobic lifestyle. Natural cellular oxidants may be involved in cell signaling and antibacterial defense; however, imbalanced levels can lead to protein misfolding, cell damage, and death. This merges together the processes of protein homeostasis and redox regulation. At the heart of this process are redox-regulated proteins or thiol-based switches, which carefully mediate various steps of protein homeostasis across folding, localization, quality control, and degradation pathways. In this review, we discuss the "redox code" of the proteostasis network, which shapes protein health during cell growth and aging. We describe the sources and types of thiol modifications and elaborate on diverse strategies of evolving antioxidant proteins in proteostasis networks during oxidative stress conditions. We also highlight the involvement of cysteines in protein degradation across varying levels, showcasing the importance of cysteine thiols in proteostasis at large. The individual examples and mechanisms raised open the door for extensive future research exploring the interplay between the redox and protein homeostasis systems. Understanding this interplay will enable us to re-write the redox code of cells and use it for biotechnological and therapeutic purposes.
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Affiliation(s)
- Meytal Radzinski
- Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Safra Campus Givat Ram, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; (M.R.); (T.O.)
| | - Tal Oppenheim
- Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Safra Campus Givat Ram, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; (M.R.); (T.O.)
| | - Norman Metanis
- Institute of Chemistry, Safra Campus Givat Ram, The Hebrew University of Jerusalem, Jerusalem 91904, Israel;
| | - Dana Reichmann
- Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Safra Campus Givat Ram, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; (M.R.); (T.O.)
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Gundogdu M, Tadayon R, Salzano G, Shaw GS, Walden H. A mechanistic review of Parkin activation. Biochim Biophys Acta Gen Subj 2021; 1865:129894. [PMID: 33753174 DOI: 10.1016/j.bbagen.2021.129894] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 03/05/2021] [Accepted: 03/18/2021] [Indexed: 11/17/2022]
Abstract
Parkin and phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) constitute a feed-forward signalling pathway that mediates autophagic removal of damaged mitochondria (mitophagy). With over 130 mutations identified to date in over 1000 patients with early onset parkinsonism, Parkin is considered a hot spot of signalling pathways involved in PD aetiology. Parkin is an E3 ligase and how its activity is regulated has been extensively studied: inter-domain interactions exert a tight inhibition on Parkin activity; binding to phospho-ubiquitin relieves this auto-inhibition; and phosphorylation of Parkin shifts the equilibrium towards maximal Parkin activation. This review focusses on recent, structural findings on the regulation of Parkin activity. What follows is a mechanistic introduction to the family of E3 ligases that includes Parkin, followed by a brief description of structural elements unique to Parkin that lock the enzyme in an autoinhibited state, contrasted with emerging models that have shed light on possible mechanisms of Parkin activation.
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Affiliation(s)
- Mehmet Gundogdu
- Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Roya Tadayon
- Department of Biochemistry, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada
| | - Giulia Salzano
- Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Gary S Shaw
- Department of Biochemistry, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada
| | - Helen Walden
- Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
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Halder T, Verma SP, Raj J, Pandey S, Singh RK, Sharma V, Joshi D, Das P. Identification & characterization of leucine-rich repeat kinase 2 & parkin RBR E3 ubiquitin protein ligase variants in patients with Parkinson's disease. Indian J Med Res 2021; 152:498-507. [PMID: 33707392 PMCID: PMC8157902 DOI: 10.4103/ijmr.ijmr_730_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Background & objectives: Parkinson's disease (PD) is a motor disorder that affects movement. More than 24 loci and 28 associated genes have been identified to be associated with this disease. The present study accounts for the contribution of two candidates, leucine-rich repeat kinase 2 (LRRK2) and parkin RBR E3 ubiquitin protein ligase (PRKN) in the PD patients, and their characterization in silico and in vitro. Methods: A total of 145 sporadic PD cases and 120 ethnically matched healthy controls were enrolled with their informed consent. Mutation screening was performed by direct DNA sequencing of the targeted exons of LRRK2 and all exons flanking introns of PRKN. The effect of the pathogenic PRKN variants on a drug (MG-132) induced loss of mitochondrial membrane potential (△ΨM) was measured by a fluorescent dye tetramethylrhodamine methyl ester (TMRM). Results: Twelve and 20 genetic variants were identified in LRRK2 and PRKN, respectively. Interestingly, five out of seven exonic LRRK2 variants were synonymous. Further assessment in controls confirmed the rarity of two such p.Y1527 and p.V1615. Among the pathogenic missense variations (as predicted in silico) in PRKN, two were selected (p.R42H and p.A82E) for their functional study in vitro, which revealed the reduced fluorescence intensity of TMRM as compared to wild type, in case of p.R42H but not the other. Interpretation & conclusions: About 6.2 per cent of the cases (9/145) in the studied patient cohort were found to carry pathogenic (as predicted in silico) missense variations in PRKN in heterozygous condition but not in case of LRRK2 which was rare. The presence of two rare synonymous variants of LRRK2 (p.Y1527 and p.V1615) may support the phenomenon of codon bias. Functional characterization of selected PRKN variations revealed p.R42H to cause disruption of mitochondrial membrane potential (△ΨM) rendering cells more susceptible to cellular stress.
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Affiliation(s)
- Tamali Halder
- Centre for Genetic Disorders, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Shiv Prakash Verma
- Centre for Genetic Disorders, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Janak Raj
- Department of Neurosurgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Sharad Pandey
- Department of Neurosurgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Ranjeet Kumar Singh
- Department of Neurology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Vivek Sharma
- Department of Neurosurgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Deepika Joshi
- Department of Neurology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Parimal Das
- Centre for Genetic Disorders, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
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40
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Liu X, Moussa C. Regulatory Role of Ubiquitin Specific Protease-13 (USP13) in Misfolded Protein Clearance in Neurodegenerative Diseases. Neuroscience 2021; 460:161-166. [PMID: 33577955 DOI: 10.1016/j.neuroscience.2021.02.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 02/02/2021] [Accepted: 02/03/2021] [Indexed: 12/14/2022]
Abstract
Ubiquitin Specific Protease (USP)-13 is a de-ubiquitinase member of the cysteine-dependent protease superfamily that cleaves ubiquitin off protein substrates to reverse ubiquitin-mediated protein degradation. Several findings implicate USPs in neurodegeneration. Ubiquitin targets proteins to major degradation pathways, including the proteasome and the lysosome. In melanoma cells, USP13 regulates the degradation of several proteins primarily via ubiquitination and de-ubiquitination. However, the significance of USP13 in regulating protein clearance in neurodegeneration is largely unknown. This mini-review summarizes the most recent evidence pertaining to the role of USP13 in protein clearance via autophagy and the proteasome in neurodegenerative diseases.
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Affiliation(s)
- Xiaoguang Liu
- Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, Building D, Room 265, 4000 Reservoir Road, NW, Washington DC 20057, USA.
| | - Charbel Moussa
- Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, Building D, Room 265, 4000 Reservoir Road, NW, Washington DC 20057, USA.
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41
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Biswas S, Bagchi A. Mutational Impact on "in-Between-Ring" (IBR) Domain of PARKIN on Protein Stability and Function. Appl Biochem Biotechnol 2021; 193:1603-1616. [PMID: 33471285 DOI: 10.1007/s12010-021-03491-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 01/07/2021] [Indexed: 11/29/2022]
Abstract
Mutations in parkin, which is encoded by the PARK2 gene, are associated with a rare form of Parkinson's disease called autosomal recessive juvenile parkinsonism (ARJP). Parkin is a member of RBR family of E3 ubiquitin ligase. Parkin contains a RING1-In-Between-Ring (IBR)-RING2 motif. The IBR domain is located at the C-terminal end of the parkin protein. Two zinc-binding sites are present in the IBR domain which shows zinc ion-dependent folding and maintains the orientation and geometry of RING domains. So, mutation in a zinc-binding region can be responsible for improper folding of parkin protein, which eventually affects the protein structure and function. Abnormalities in parkin protein increase the aggregation of mis-folded proteins in the brain cell. As a consequence, cellular toxicity occurs. The IBR domain also interacts with UbcH7 and UbcH8 proteins belonging to E2 protein family and facilitates synphilin-1, Sept5, and SIM2 protein ubiquitination. It is reported that missense mutation in parkin protein are responsible for autosomal recessive juvenile Parkinson disease. In this work, we first collected the missense mutations in the IBR domain from literature and sequence databases. Then, using various computational tools, we predicted their pathogenicity and involvements in causing possible changes in various protein properties. Evolutionary conservation of amino acids, solvent accessible surface areas, the physico-chemical properties, and changes of protein structure were analyzed. We, for the first time, analyzed the effects of these mutations in parkin to decipher the plausible molecular mechanism of Parkinson's disease.
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Affiliation(s)
- Sima Biswas
- Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, Nadia, West Bengal, 741235, India
| | - Angshuman Bagchi
- Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, Nadia, West Bengal, 741235, India.
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42
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Wang Y, Yan S, Zhang F, Li J, Li R, Zhang CX. Parkin-dependent and -independent degradation of synaptotagmin-11 in neurons and astrocytes. Neurosci Lett 2020; 739:135402. [PMID: 32976921 DOI: 10.1016/j.neulet.2020.135402] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 09/13/2020] [Accepted: 09/19/2020] [Indexed: 11/29/2022]
Abstract
Synaptotagmin-11 (Syt11) is associated with schizophrenia and Parkinson's disease (PD) and is a critical substrate of parkin, an E3 ubiquitin ligase linked to PD. Previously we reported that Syt11 regulates multiple membrane trafficking pathways in neurons and glia. However, the regulation of Syt11 degradation remains largely unknown. As the ubiquitin-proteasome pathway (UPP) plays crucial roles in protein degradation and quality control, we investigated UPP-dependent Syt11 degradation in this study. We found that Syt11 is a short-lived protein with a half-life of 1.49 h in the presence of a protein synthesis inhibitor cycloheximide and is mainly degraded by UPP in neurons. The degradation was further accelerated under sustained neuronal activity and was parkin-dependent. Interestingly, Syt11 had a faster turnover in astrocytes with a half-life of 0.58 h, and UPP partially contributed to its degradation. Mechanical stress applied on astrocytes by hypoosmotic treatment led to reduced Syt11 protein level but increased parkin level. However, the degradation of Syt11 was parkin-independent under both isoosmotic and hypoosmotic condition. Altogether, our results revealed active and distinct proteolytic regulation of Syt11 in neurons and astrocytes.
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Affiliation(s)
- Yalong Wang
- Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing 100069, China
| | - Shuxin Yan
- Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing 100069, China.
| | - Feifan Zhang
- Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing 100069, China
| | - Jingchen Li
- Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing 100069, China
| | - Rena Li
- Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital and Beijing Institute of Brain Disorders, Capital Medical University, Beijing 100069, China
| | - Claire Xi Zhang
- Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing 100069, China.
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43
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Marttinen M, Ferreira CB, Paldanius KMA, Takalo M, Natunen T, Mäkinen P, Leppänen L, Leinonen V, Tanigaki K, Kang G, Hiroi N, Soininen H, Rilla K, Haapasalo A, Hiltunen M. Presynaptic Vesicle Protein SEPTIN5 Regulates the Degradation of APP C-Terminal Fragments and the Levels of Aβ. Cells 2020; 9:cells9112482. [PMID: 33203136 PMCID: PMC7696542 DOI: 10.3390/cells9112482] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 11/05/2020] [Accepted: 11/10/2020] [Indexed: 12/28/2022] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease characterized by aberrant amyloid-β (Aβ) and hyperphosphorylated tau aggregation. We have previously investigated the involvement of SEPTIN family members in AD-related cellular processes and discovered a role for SEPTIN8 in the sorting and accumulation of β-secretase. Here, we elucidated the potential role of SEPTIN5, an interaction partner of SEPTIN8, in the cellular processes relevant for AD, including amyloid precursor protein (APP) processing and the generation of Aβ. The in vitro and in vivo studies both revealed that the downregulation of SEPTIN5 reduced the levels of APP C-terminal fragments (APP CTFs) and Aβ in neuronal cells and in the cortex of Septin5 knockout mice. Mechanistic elucidation revealed that the downregulation of SEPTIN5 increased the degradation of APP CTFs, without affecting the secretory pathway-related trafficking or the endocytosis of APP. Furthermore, we found that the APP CTFs were degraded, to a large extent, via the autophagosomal pathway and that the downregulation of SEPTIN5 enhanced autophagosomal activity in neuronal cells as indicated by altered levels of key autophagosomal markers. Collectively, our data suggest that the downregulation of SEPTIN5 increases the autophagy-mediated degradation of APP CTFs, leading to reduced levels of Aβ in neuronal cells.
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Affiliation(s)
- Mikael Marttinen
- Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland; (M.M.); (K.M.A.P.); (M.T.); (T.N.); (P.M.); (L.L.); (K.R.)
| | - Catarina B. Ferreira
- Instituto de Medicina Molecular—João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal;
| | - Kaisa M. A. Paldanius
- Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland; (M.M.); (K.M.A.P.); (M.T.); (T.N.); (P.M.); (L.L.); (K.R.)
| | - Mari Takalo
- Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland; (M.M.); (K.M.A.P.); (M.T.); (T.N.); (P.M.); (L.L.); (K.R.)
| | - Teemu Natunen
- Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland; (M.M.); (K.M.A.P.); (M.T.); (T.N.); (P.M.); (L.L.); (K.R.)
| | - Petra Mäkinen
- Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland; (M.M.); (K.M.A.P.); (M.T.); (T.N.); (P.M.); (L.L.); (K.R.)
| | - Luukas Leppänen
- Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland; (M.M.); (K.M.A.P.); (M.T.); (T.N.); (P.M.); (L.L.); (K.R.)
| | - Ville Leinonen
- Institute of Clinical Medicine–Neurosurgery, University of Eastern Finland, 70210 Kuopio, Finland;
- Neurology of Neuro Center Kuopio University Hospital, 70210 Kuopio, Finland
| | - Kenji Tanigaki
- Research Institute, Shiga Medical Center, Shiga 524-8524, Japan;
| | - Gina Kang
- Department of Pharmacology, Department of Integrative and Systems Physiology, Department of Cell Systems and Anatomy, Department of Psychiatry, University of Texas Health Science Center, San Antonio, TX 77030, USA; (G.K.); (N.H.)
| | - Noboru Hiroi
- Department of Pharmacology, Department of Integrative and Systems Physiology, Department of Cell Systems and Anatomy, Department of Psychiatry, University of Texas Health Science Center, San Antonio, TX 77030, USA; (G.K.); (N.H.)
| | - Hilkka Soininen
- Institute of Clinical Medicine–Neurology, University of Eastern Finland, 70210 Kuopio, Finland;
| | - Kirsi Rilla
- Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland; (M.M.); (K.M.A.P.); (M.T.); (T.N.); (P.M.); (L.L.); (K.R.)
| | - Annakaisa Haapasalo
- A.I Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70210 Kuopio, Finland
- Correspondence: (A.H.); (M.H.); Tel.: +358-40-355-2768 (A.H.); +358-40-355-2014 (M.H.)
| | - Mikko Hiltunen
- Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland; (M.M.); (K.M.A.P.); (M.T.); (T.N.); (P.M.); (L.L.); (K.R.)
- Correspondence: (A.H.); (M.H.); Tel.: +358-40-355-2768 (A.H.); +358-40-355-2014 (M.H.)
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Feng J. Modeling the pathophysiology of Parkinson's disease in patient-specific neurons. Exp Biol Med (Maywood) 2020; 246:298-304. [PMID: 32972199 DOI: 10.1177/1535370220961788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
The 30 trillion cells that self-assemble into a human being originate from the pluripotent stem cells in the inner cell mass of a human blastocyst. The discovery of induced pluripotent stem cells (iPSCs) makes it possible to approximate various aspects of this natural developmental process artificially by generating materials that can be used in invasive mechanistic studies of virtually all human conditions. In Parkinson's disease, instructions computed by the basal ganglia to control voluntary motor functions break down, leading to widespread rhythmic bursting activities in the basal ganglia and beyond. It is thought that these oscillatory neuronal activities, which disrupt aperiodic neurotransmission in a normal brain, may reduce information content in the instructions for motor control. Using midbrain neuronal cultures differentiated from iPSCs of Parkinson's disease patients with parkin mutations, we find that parkin mutations cause oscillatory neuronal activities when dopamine D1-class receptors are activated. This system makes it possible to study the molecular basis of rhythmic bursting activities in Parkinson's disease. Further development of stem cell models of Parkinson's disease will enable better approximation of the situation in the brain of Parkinson's disease patients. In this review, I will discuss what has been found in the past about the pathophysiology of motor dysfunction in Parkinson's disease, especially oscillatory neuronal activities and how stem cell technologies may transform our abilities to understand the pathophysiology of Parkinson's disease.
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Affiliation(s)
- Jian Feng
- Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14203, USA
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45
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Trinh D, Israwi AR, Arathoon LR, Gleave JA, Nash JE. The multi-faceted role of mitochondria in the pathology of Parkinson's disease. J Neurochem 2020; 156:715-752. [PMID: 33616931 DOI: 10.1111/jnc.15154] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 07/29/2020] [Accepted: 07/31/2020] [Indexed: 12/14/2022]
Abstract
Mitochondria are essential for neuronal function. They produce ATP to meet energy demands, regulate homeostasis of ion levels such as calcium and regulate reactive oxygen species that cause oxidative cellular stress. Mitochondria have also been shown to regulate protein synthesis within themselves, as well as within the nucleus, and also influence synaptic plasticity. These roles are especially important for neurons, which have higher energy demands and greater susceptibility to stress. Dysfunction of mitochondria has been associated with several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, Glaucoma and Amyotrophic Lateral Sclerosis. The focus of this review is on how and why mitochondrial function is linked to the pathology of Parkinson's disease (PD). Many of the PD-linked genetic mutations which have been identified result in dysfunctional mitochondria, through a wide-spread number of mechanisms. In this review, we describe how susceptible neurons are predisposed to be vulnerable to the toxic events that occur during the neurodegenerative process of PD, and how mitochondria are central to these pathways. We also discuss ways in which proteins linked with familial PD control mitochondrial function, both physiologically and pathologically, along with their implications in genome-wide association studies and risk assessment. Finally, we review potential strategies for disease modification through mitochondrial enhancement. Ultimately, agents capable of both improving and/or restoring mitochondrial function, either alone, or in conjunction with other disease-modifying agents may halt or slow the progression of neurodegeneration in Parkinson's disease.
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Affiliation(s)
- Dennison Trinh
- Department of Biological Sciences, University of Toronto Scarborough, Centre for Neurobiology of Stress, Toronto, ON, Canada
| | - Ahmad R Israwi
- Department of Biological Sciences, University of Toronto Scarborough, Centre for Neurobiology of Stress, Toronto, ON, Canada
| | - Lindsay R Arathoon
- Department of Biological Sciences, University of Toronto Scarborough, Centre for Neurobiology of Stress, Toronto, ON, Canada
| | - Jacqueline A Gleave
- Department of Biological Sciences, University of Toronto Scarborough, Centre for Neurobiology of Stress, Toronto, ON, Canada
| | - Joanne E Nash
- Department of Biological Sciences, University of Toronto Scarborough, Centre for Neurobiology of Stress, Toronto, ON, Canada
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46
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Ding D, Ao X, Li M, Miao S, Liu Y, Lin Z, Wang M, He Y, Wang J. FOXO3a-dependent Parkin regulates the development of gastric cancer by targeting ATP-binding cassette transporter E1. J Cell Physiol 2020; 236:2740-2755. [PMID: 32914432 DOI: 10.1002/jcp.30040] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Revised: 08/20/2020] [Accepted: 08/24/2020] [Indexed: 01/12/2023]
Abstract
Gastric cancer (GC) is one of the most common malignant tumors in China and the third leading cause of cancer-related death. Parkin has been shown to be a tumor suppressor in a variety of malignancies, including GC. However, the mechanism of Parkin in GC remains unclear. In this study, the low expression of Parkin in GC cells and patient tumor tissues was observed, and Parkin inhibited proliferation and migration of GC cells. Additionally, doxorubicin (DOX) upregulated the expression of Parkin and promoted its anticancer effect. Forkhead box O3 (FOXO3a) is a crucial transcription factor that involves in the regulation of cancer cell proliferation, apoptosis, and metabolism. Here, we found that FOXO3a inhibits cell proliferation, migration, and promotes apoptosis in GC by regulating Parkin expression at the transcriptional level. In addition, Parkin inhibited cell proliferation, migration, and promoted apoptosis by inhibiting ATP-binding box protein E1 (ABCE1) expression. In summary, our results demonstrated a new regulatory axis of FOXO3a-Parkin-ABCE1 that modulated GC cell proliferation, migration, and apoptosis, and it can serve as a potential therapeutic target in GC.
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Affiliation(s)
- Dan Ding
- School of Basic Medical Sciences, College of Medicine, Qingdao University, Qingdao, China.,Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Xiang Ao
- School of Basic Medical Sciences, College of Medicine, Qingdao University, Qingdao, China.,Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Mengyang Li
- School of Basic Medical Sciences, College of Medicine, Qingdao University, Qingdao, China
| | - Shuo Miao
- School of Basic Medical Sciences, College of Medicine, Qingdao University, Qingdao, China.,Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Ying Liu
- School of Basic Medical Sciences, College of Medicine, Qingdao University, Qingdao, China.,Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Zhijuan Lin
- Key Lab for Immunology in Universities of Shandong Province, School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Mengyu Wang
- School of Basic Medical Sciences, College of Medicine, Qingdao University, Qingdao, China.,Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Yuqi He
- Department of Gastroenterology, Seventh Medical Center of Chinese PLA General Hospital, Beijing, China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Jianxun Wang
- School of Basic Medical Sciences, College of Medicine, Qingdao University, Qingdao, China.,Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
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47
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Brahmachari S, Lee S, Kim S, Yuan C, Karuppagounder SS, Ge P, Shi R, Kim EJ, Liu A, Kim D, Quintin S, Jiang H, Kumar M, Yun SP, Kam TI, Mao X, Lee Y, Swing DA, Tessarollo L, Ko HS, Dawson VL, Dawson TM. Parkin interacting substrate zinc finger protein 746 is a pathological mediator in Parkinson's disease. Brain 2020; 142:2380-2401. [PMID: 31237944 DOI: 10.1093/brain/awz172] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 04/16/2019] [Accepted: 04/23/2019] [Indexed: 12/22/2022] Open
Abstract
α-Synuclein misfolding and aggregation plays a major role in the pathogenesis of Parkinson's disease. Although loss of function mutations in the ubiquitin ligase, parkin, cause autosomal recessive Parkinson's disease, there is evidence that parkin is inactivated in sporadic Parkinson's disease. Whether parkin inactivation is a driver of neurodegeneration in sporadic Parkinson's disease or a mere spectator is unknown. Here we show that parkin in inactivated through c-Abelson kinase phosphorylation of parkin in three α-synuclein-induced models of neurodegeneration. This results in the accumulation of parkin interacting substrate protein (zinc finger protein 746) and aminoacyl tRNA synthetase complex interacting multifunctional protein 2 with increased parkin interacting substrate protein levels playing a critical role in α-synuclein-induced neurodegeneration, since knockout of parkin interacting substrate protein attenuates the degenerative process. Thus, accumulation of parkin interacting substrate protein links parkin inactivation and α-synuclein in a common pathogenic neurodegenerative pathway relevant to both sporadic and familial forms Parkinson's disease. Thus, suppression of parkin interacting substrate protein could be a potential therapeutic strategy to halt the progression of Parkinson's disease and related α-synucleinopathies.
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Affiliation(s)
- Saurav Brahmachari
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Saebom Lee
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Sangjune Kim
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Changqing Yuan
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Senthilkumar S Karuppagounder
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Preston Ge
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Rosa Shi
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Esther J Kim
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Alex Liu
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Donghoon Kim
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Stephan Quintin
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Haisong Jiang
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Manoj Kumar
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Seung Pil Yun
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Tae-In Kam
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Xiaobo Mao
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Yunjong Lee
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Deborah A Swing
- Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
| | - Lino Tessarollo
- Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
| | - Han Seok Ko
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Valina L Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.,Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Ted M Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.,Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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48
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Abstract
Discovery of Park2 is our finding of a family of young onset parkinsonism, in which this family was thought to be associated with a polymorphism of the manganese superoxide gene. The gene locus of the manganese superoxide dismutase has been known. We were able to pick up a gene for this family and related families in the close approximate position at the long arm of chromosome 6. The gene for this disease has a ubiquitin-like motif in the N-terminus and two RING finger structures. It was shown that this gene had a ubiquitin-protein ligase activity. But it is not elucidated the substrate of this enzyme. Meanwhile, it has become clear that PINK1 and Parkin work together to remove the mitochondria of the lowered membrane potential in the autophagosomes (mitophagy). Now that the molecular mechanisms of mitophagy is under investigation. In addition, many hot topics are going on such as Lewy body in Park2, single heterozygotes, rare clinical manifestations, and so on.
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Affiliation(s)
- Yoshikuni Mizuno
- Department of Neurology, Juntendo University Japan; Department of Neurology, Tokyo Clinic Japan.
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49
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Chen K, Chen J, Wang L, Yang J, Xiao F, Wang X, Yuan J, Wang L, He Y. Parkin ubiquitinates GATA4 and attenuates the GATA4/GAS1 signaling and detrimental effects on diabetic nephropathy. FASEB J 2020; 34:8858-8875. [PMID: 32436607 DOI: 10.1096/fj.202000053r] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 04/13/2020] [Accepted: 05/05/2020] [Indexed: 01/26/2023]
Abstract
Renal tubular injury contributes to the progression of diabetic nephropathy (DN). This study explored the role and mechanisms of E3-ubiquitin ligase Parkin in the renal tubular injury of DN. We found that Parkin expression gradually decreased and was inversely associated with IL-6, TGF-β1, and GATA4 expression in the kidney during the progression of DN. Parkin over-expression (OE) reduced inflammation, fibrosis, premature senescence of renal tubular epithelial cells (RTECs), and improved renal function while Parkin knockout (KO) had opposite effects in DN mice. Parkin-OE decreased GATA4 protein, but not its mRNA transcripts in the kidney of DN mice and high glucose (HG)-treated RTECs. Immunoprecipitation indicated that Parkin directly interacted with GATA4 in DN kidney. Parkin-OE enhanced GATA4 ubiquitination. Furthermore, Parkin-KO upregulated growth arrest-specific gene 1 (GAS1) expression in renal tubular tissues of DN mice and GATA4-OE enhanced the HG-upregulated GAS1 expression in RTECs. Conversely, GAS1-OE mitigated the effect of Parkin-OE on HG-induced P21, IL-6, and TGF-β1 expression in RTECs. These results indicate that Parkin inhibits the progression of DN by promoting GATA4 ubiquitination and downregulating the GATA4/GAS1 signaling to inhibit premature senescence, inflammation, and fibrosis in DN mice. Thus, these findings uncover new mechanisms underlying the action of Parkin during the process of DN.
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Affiliation(s)
- Kehong Chen
- Department of Nephrology, Daping Hospital, Army Medical University, Chongqing, China
| | - Jia Chen
- Department of Nephrology, Daping Hospital, Army Medical University, Chongqing, China
| | - Ling Wang
- Department of Nephrology, Daping Hospital, Army Medical University, Chongqing, China
| | - Jie Yang
- Department of Nephrology, Daping Hospital, Army Medical University, Chongqing, China
| | - Fei Xiao
- Department of Nephrology, Daping Hospital, Army Medical University, Chongqing, China
| | - Xianyue Wang
- Department of Nephrology, Daping Hospital, Army Medical University, Chongqing, China
| | - Junjie Yuan
- Department of Nephrology, Daping Hospital, Army Medical University, Chongqing, China
| | - Limin Wang
- Department of Nephrology, Daping Hospital, Army Medical University, Chongqing, China
| | - Yani He
- Department of Nephrology, Daping Hospital, Army Medical University, Chongqing, China
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50
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Hoffmann-Conaway S, Brockmann MM, Schneider K, Annamneedi A, Rahman KA, Bruns C, Textoris-Taube K, Trimbuch T, Smalla KH, Rosenmund C, Gundelfinger ED, Garner CC, Montenegro-Venegas C. Parkin contributes to synaptic vesicle autophagy in Bassoon-deficient mice. eLife 2020; 9:56590. [PMID: 32364493 PMCID: PMC7224700 DOI: 10.7554/elife.56590] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 05/02/2020] [Indexed: 12/18/2022] Open
Abstract
Mechanisms regulating the turnover of synaptic vesicle (SV) proteins are not well understood. They are thought to require poly-ubiquitination and degradation through proteasome, endo-lysosomal or autophagy-related pathways. Bassoon was shown to negatively regulate presynaptic autophagy in part by scaffolding Atg5. Here, we show that increased autophagy in Bassoon knockout neurons depends on poly-ubiquitination and that the loss of Bassoon leads to elevated levels of ubiquitinated synaptic proteins per se. Our data show that Bassoon knockout neurons have a smaller SV pool size and a higher turnover rate as indicated by a younger pool of SV2. The E3 ligase Parkin is required for increased autophagy in Bassoon-deficient neurons as the knockdown of Parkin normalized autophagy and SV protein levels and rescued impaired SV recycling. These data indicate that Bassoon is a key regulator of SV proteostasis and that Parkin is a key E3 ligase in the autophagy-mediated clearance of SV proteins.
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Affiliation(s)
| | - Marisa M Brockmann
- Charité - Universitätsmedizin Berlin, Institute of Neurobiology, Berlin, Germany.,NeuroCure Cluster of Excellence, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | | | - Anil Annamneedi
- Leibniz Institute for Neurobiology, Magdeburg, Germany.,Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany.,Institute of Biology (IBIO), Otto von Guericke University Magdeburg, Magdeburg, Germany
| | - Kazi Atikur Rahman
- German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.,Einstein Center for Neurosciences Berlin, Berlin, Germany
| | - Christine Bruns
- German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany
| | - Kathrin Textoris-Taube
- Charité - Universitätsmedizin Berlin, Institute of Biochemistry, Core Facility High Throughput Mass Spectrometry, Berlin, Germany
| | - Thorsten Trimbuch
- Charité - Universitätsmedizin Berlin, Institute of Neurobiology, Berlin, Germany.,NeuroCure Cluster of Excellence, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Karl-Heinz Smalla
- Leibniz Institute for Neurobiology, Magdeburg, Germany.,Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany
| | - Christian Rosenmund
- Charité - Universitätsmedizin Berlin, Institute of Neurobiology, Berlin, Germany.,NeuroCure Cluster of Excellence, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Eckart D Gundelfinger
- Leibniz Institute for Neurobiology, Magdeburg, Germany.,Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany.,Molecular Neurobiology, Medical Faculty, Otto von Guericke University, Magdeburg, Germany
| | - Craig Curtis Garner
- German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.,Charité - Universitätsmedizin Berlin, Institute of Neurobiology, Berlin, Germany.,NeuroCure Cluster of Excellence, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Carolina Montenegro-Venegas
- Leibniz Institute for Neurobiology, Magdeburg, Germany.,Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany.,Institute for Pharmacology and Toxicology, Medical Faculty, Otto von Guericke University, Magdeburg, Germany
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