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Cukkemane A, Dingley AJ, Mohrlüder J, Santiago-Schübel B, Weiergräber OH, Willbold D. A peptide mimetic therapeutic strategy targeting dysfunction of the scaffold protein DISC-1 in psychiatric disorders. Eur J Pharm Sci 2025; 211:107148. [PMID: 40449672 DOI: 10.1016/j.ejps.2025.107148] [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: 04/28/2025] [Revised: 05/16/2025] [Accepted: 05/28/2025] [Indexed: 06/03/2025]
Abstract
Disrupted in schizophrenia 1 (DISC1) is a scaffold protein that regulates several physiological processes ranging from cellular division to neurodevelopment, and its dysfunction contributes to various neurological disorders including schizophrenia, bipolar and mood disorders, and autism. Thus, deciphering its native functions and pathophysiological roles is crucial. In this report, three disease-associated mutants of the C-region of DISC1, i.e., S713E, S704C, and L807-frameshift, were examined to further elucidate the role of DISC1 in cell division. We demonstrate that the mutations do not render the variants functionally inactive; instead, the interaction sites are presumably lost during the aggregation of the DISC1 C-region into amyloid-type fibrils. The minimal fibrillizing element in the C-region is the intrinsically disordered β-core (716‒761) that houses a segment absent in the splice variant DISC1Δ22aa, which cannot bind proteins of the mitotic spindle complex and thus hampers cellular proliferation. Based on these structure-function relationships, we present a rational drug development strategy using phage display technology and highlight the role of peptide mimetics in curtailing the agglomeration of fibrils.
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Affiliation(s)
- Abhishek Cukkemane
- Institute of Biological Information Processing, Structural Biochemistry (IBI-7), Forschungszentrum Jülich, Jülich, Germany.; Heinrich Heine University Düsseldorf, Institut für Physikalische Biologie, Düsseldorf, Germany..
| | - Andrew J Dingley
- Institute of Biological Information Processing, Structural Biochemistry (IBI-7), Forschungszentrum Jülich, Jülich, Germany
| | - Jeannine Mohrlüder
- Institute of Biological Information Processing, Structural Biochemistry (IBI-7), Forschungszentrum Jülich, Jülich, Germany
| | - Beatrix Santiago-Schübel
- Institute of Biological Information Processing, Structural Biochemistry (IBI-7), Forschungszentrum Jülich, Jülich, Germany
| | - Oliver H Weiergräber
- Institute of Biological Information Processing, Structural Biochemistry (IBI-7), Forschungszentrum Jülich, Jülich, Germany..
| | - Dieter Willbold
- Institute of Biological Information Processing, Structural Biochemistry (IBI-7), Forschungszentrum Jülich, Jülich, Germany.; Heinrich Heine University Düsseldorf, Institut für Physikalische Biologie, Düsseldorf, Germany..
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2
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Lal S, Snape TJ. Tubulin targeting agents and their implications in non-cancer disease management. Drug Discov Today 2025; 30:104338. [PMID: 40118444 DOI: 10.1016/j.drudis.2025.104338] [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: 07/26/2024] [Revised: 03/05/2025] [Accepted: 03/14/2025] [Indexed: 03/23/2025]
Abstract
Microtubules act as molecular 'tracks' for the intracellular transport of accessory proteins, enabling them to assemble into various larger structures, such as spindle fibres formed during the cell cycle. Microtubules provide an organisational framework for the healthy functioning of various cellular processes that work through the process of dynamic instability, driven by the hydrolysis of GTP. In this role, tubulin proteins undergo various modifications, and in doing so modulate various healthy or pathogenic physiological processes within cells. In this review, we provide a detailed update of small molecule chemical agents that interact with tubulin, along with their implications, specifically in non-cancer disease management.
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Affiliation(s)
- Samridhi Lal
- Amity Institute of Pharmacy, Amity University, Gurugram 122413 Haryana, India.
| | - Timothy J Snape
- Leicester School of Pharmacy, De Montfort University, Leicester LE1 9BH, UK
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Ma D, Gu C. Discovering functional interactions among schizophrenia-risk genes by combining behavioral genetics with cell biology. Neurosci Biobehav Rev 2024; 167:105897. [PMID: 39278606 PMCID: PMC12057806 DOI: 10.1016/j.neubiorev.2024.105897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 08/26/2024] [Accepted: 09/13/2024] [Indexed: 09/18/2024]
Abstract
Despite much progress in identifying risk genes for polygenic brain disorders, their core pathogenic mechanisms remain poorly understood. In particular, functions of many proteins encoded by schizophrenia risk genes appear diverse and unrelated, complicating the efforts to establish the causal relationship between genes and behavior. Using various mouse lines, recent studies indicate that alterations of parvalbumin-positive (PV+) GABAergic interneurons can lead to schizophrenia-like behavior. PV+ interneurons display fast spiking and contribute to excitation-inhibition balance and network oscillations via feedback and feedforward inhibition. Here, we first summarize different lines of genetically modified mice that display motor, cognitive, emotional, and social impairments used to model schizophrenia and related mental disorders. We highlight ten genes, encoding either a nuclear, cytosolic, or membrane protein. Next, we discuss their functional relationship in regulating fast spiking and other aspects of PV+ interneurons and in the context of other domains of schizophrenia. Future investigations combining behavioral genetics and cell biology should elucidate functional relationships among risk genes to identify the core pathogenic mechanisms underlying polygenic brain disorders.
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Affiliation(s)
- Di Ma
- Ohio State Biochemistry Graduate Program, The Ohio State University, Columbus, OH 43210, USA
| | - Chen Gu
- Ohio State Biochemistry Graduate Program, The Ohio State University, Columbus, OH 43210, USA; Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH 43210, USA.
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Furukawa S, Arafuka S, Kato H, Ogi T, Ozaki N, Ikeda M, Kushima I. Treatment-resistant schizophrenia with 22q11.2 deletion and additional genetic defects. Neuropsychopharmacol Rep 2024. [PMID: 39189429 DOI: 10.1002/npr2.12477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 08/02/2024] [Accepted: 08/15/2024] [Indexed: 08/28/2024] Open
Abstract
We report a case of a 61-year-old female with 22q11.2 deletion syndrome (22q11.2DS) and a novel heterozygous nonsense variant in MAP1A, identified through whole-genome sequencing (WGS). The patient presented with intellectual developmental disorder, treatment-resistant schizophrenia (SCZ), and multiple congenital anomalies. Despite aggressive pharmacotherapy, she experienced persistent auditory hallucinations and negative symptoms. WGS revealed a 3 Mb deletion at 22q11.2 and a nonsense variant in MAP1A (c.4652T>G, p.Leu1551*). MAP1A, encoding microtubule-associated protein 1A, is crucial for axon and dendrite development and has been implicated in autism spectrum disorder and SCZ. The MAP1A variant may contribute to the severe psychiatric phenotype, as it is thought to influence synaptic plasticity, a process also affected by 22q11.2 deletion. This case highlights the importance of WGS in identifying additional pathogenic variants that may explain phenotypic variability in 22q11.2DS. Thus, WGS can lead to a better understanding of the genetic architecture of 22q11.2DS. However, further studies are needed to elucidate the role of secondary genetic contributors in the diverse clinical presentations of 22q11.2DS.
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Affiliation(s)
- Sawako Furukawa
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shusei Arafuka
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hidekazu Kato
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Psychiatry for Parents and Children, Nagoya University Hospital, Nagoya, Japan
| | - Tomoo Ogi
- Department of Genetics, Research Institute of Environmental Medicine (RIeM), Nagoya University, Nagoya, Japan
| | - Norio Ozaki
- Pathophysiology of Mental Disorders, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masashi Ikeda
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Itaru Kushima
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Medical Genomics Center, Nagoya University Hospital, Nagoya, Japan
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Samardžija B, Petrović M, Zaharija B, Medija M, Meštrović A, Bradshaw NJ, Filošević Vujnović A, Andretić Waldowski R. Transgenic Drosophila melanogaster Carrying a Human Full-Length DISC1 Construct (UAS- hflDISC1) Showing Effects on Social Interaction Networks. Curr Issues Mol Biol 2024; 46:8526-8549. [PMID: 39194719 DOI: 10.3390/cimb46080502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/29/2024] Open
Abstract
Disrupted in Schizophrenia 1 (DISC1) is a scaffold protein implicated in major mental illnesses including schizophrenia, with a significant negative impact on social life. To investigate if DISC1 affects social interactions in Drosophila melanogaster, we created transgenic flies with second or third chromosome insertions of the human full-length DISC1 (hflDISC1) gene fused to a UAS promotor (UAS-hflDISC1). Initial characterization of the insertion lines showed unexpected endogenous expression of the DISC1 protein that led to various behavioral and neurochemical phenotypes. Social interaction network (SIN) analysis showed altered social dynamics and organizational structures. This was in agreement with the altered levels of the locomotor activity of individual flies monitored for 24 h. Together with a decreased ability to climb vertical surfaces, the observed phenotypes indicate altered motor functions that could be due to a change in the function of the motor neurons and/or central brain. The changes in social behavior and motor function suggest that the inserted hflDISC1 gene influences nervous system functioning that parallels symptoms of DISC1-related mental diseases in humans. Furthermore, neurochemical analyses of transgenic lines revealed increased levels of hydrogen peroxide and decreased levels of glutathione, indicating an impact of DISC1 on the dynamics of redox regulation, similar to that reported in transgenic mammals. Future studies are needed to address the localization of DISC1 expression and to address how the redox parameter changes correlate with the observed behavioral changes.
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Affiliation(s)
- Bobana Samardžija
- Faculty of Biotechnology and Drug Development, University of Rijeka, Radmile Matejčić 2, 51 000 Rijeka, Croatia
| | - Milan Petrović
- Faculty of Informatics and Digital Technologies, University of Rijeka, Radmile Matejčić 2, 51 000 Rijeka, Croatia
| | - Beti Zaharija
- Faculty of Biotechnology and Drug Development, University of Rijeka, Radmile Matejčić 2, 51 000 Rijeka, Croatia
| | - Marta Medija
- Faculty of Biotechnology and Drug Development, University of Rijeka, Radmile Matejčić 2, 51 000 Rijeka, Croatia
| | - Ana Meštrović
- Faculty of Informatics and Digital Technologies, University of Rijeka, Radmile Matejčić 2, 51 000 Rijeka, Croatia
| | - Nicholas J Bradshaw
- Faculty of Biotechnology and Drug Development, University of Rijeka, Radmile Matejčić 2, 51 000 Rijeka, Croatia
| | - Ana Filošević Vujnović
- Faculty of Biotechnology and Drug Development, University of Rijeka, Radmile Matejčić 2, 51 000 Rijeka, Croatia
| | - Rozi Andretić Waldowski
- Faculty of Biotechnology and Drug Development, University of Rijeka, Radmile Matejčić 2, 51 000 Rijeka, Croatia
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Chandrashekar PB, Alatkar S, Wang J, Hoffman GE, He C, Jin T, Khullar S, Bendl J, Fullard JF, Roussos P, Wang D. DeepGAMI: deep biologically guided auxiliary learning for multimodal integration and imputation to improve genotype-phenotype prediction. Genome Med 2023; 15:88. [PMID: 37904203 PMCID: PMC10617196 DOI: 10.1186/s13073-023-01248-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 10/16/2023] [Indexed: 11/01/2023] Open
Abstract
BACKGROUND Genotypes are strongly associated with disease phenotypes, particularly in brain disorders. However, the molecular and cellular mechanisms behind this association remain elusive. With emerging multimodal data for these mechanisms, machine learning methods can be applied for phenotype prediction at different scales, but due to the black-box nature of machine learning, integrating these modalities and interpreting biological mechanisms can be challenging. Additionally, the partial availability of these multimodal data presents a challenge in developing these predictive models. METHOD To address these challenges, we developed DeepGAMI, an interpretable neural network model to improve genotype-phenotype prediction from multimodal data. DeepGAMI leverages functional genomic information, such as eQTLs and gene regulation, to guide neural network connections. Additionally, it includes an auxiliary learning layer for cross-modal imputation allowing the imputation of latent features of missing modalities and thus predicting phenotypes from a single modality. Finally, DeepGAMI uses integrated gradient to prioritize multimodal features for various phenotypes. RESULTS We applied DeepGAMI to several multimodal datasets including genotype and bulk and cell-type gene expression data in brain diseases, and gene expression and electrophysiology data of mouse neuronal cells. Using cross-validation and independent validation, DeepGAMI outperformed existing methods for classifying disease types, and cellular and clinical phenotypes, even using single modalities (e.g., AUC score of 0.79 for Schizophrenia and 0.73 for cognitive impairment in Alzheimer's disease). CONCLUSION We demonstrated that DeepGAMI improves phenotype prediction and prioritizes phenotypic features and networks in multiple multimodal datasets in complex brains and brain diseases. Also, it prioritized disease-associated variants, genes, and regulatory networks linked to different phenotypes, providing novel insights into the interpretation of gene regulatory mechanisms. DeepGAMI is open-source and available for general use.
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Affiliation(s)
- Pramod Bharadwaj Chandrashekar
- Waisman Center, University of Wisconsin-Madison, Madison, WI, 53705, USA
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, 53076, USA
| | - Sayali Alatkar
- Waisman Center, University of Wisconsin-Madison, Madison, WI, 53705, USA
- Department of Computer Sciences, University of Wisconsin-Madison, Madison, WI, 53076, USA
| | - Jiebiao Wang
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Gabriel E Hoffman
- Center for Disease Neurogenomics, Department of Psychiatry and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Chenfeng He
- Waisman Center, University of Wisconsin-Madison, Madison, WI, 53705, USA
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, 53076, USA
| | - Ting Jin
- Waisman Center, University of Wisconsin-Madison, Madison, WI, 53705, USA
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, 53076, USA
| | - Saniya Khullar
- Waisman Center, University of Wisconsin-Madison, Madison, WI, 53705, USA
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, 53076, USA
| | - Jaroslav Bendl
- Center for Disease Neurogenomics, Department of Psychiatry and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - John F Fullard
- Center for Disease Neurogenomics, Department of Psychiatry and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Panos Roussos
- Center for Disease Neurogenomics, Department of Psychiatry and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Mental Illness Research, Education and Clinical Centers, James J. Peters VA Medical Center, Bronx, NY, 10468, USA
- Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, 10962, USA
| | - Daifeng Wang
- Waisman Center, University of Wisconsin-Madison, Madison, WI, 53705, USA.
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, 53076, USA.
- Department of Computer Sciences, University of Wisconsin-Madison, Madison, WI, 53076, USA.
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Samardžija B, Juković M, Zaharija B, Renner É, Palkovits M, Bradshaw NJ. Co-Aggregation and Parallel Aggregation of Specific Proteins in Major Mental Illness. Cells 2023; 12:1848. [PMID: 37508512 PMCID: PMC10378145 DOI: 10.3390/cells12141848] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 07/12/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND Disrupted proteostasis is an emerging area of research into major depressive disorder. Several proteins have been implicated as forming aggregates specifically in the brains of subsets of patients with psychiatric illnesses. These proteins include CRMP1, DISC1, NPAS3 and TRIOBP-1. It is unclear, however, whether these proteins normally aggregate together in the same individuals and, if so, whether each protein aggregates independently of each other ("parallel aggregation") or if the proteins physically interact and aggregate together ("co-aggregation"). MATERIALS AND METHODS Post mortem insular cortex samples from major depressive disorder and Alzheimer's disease patients, suicide victims and control individuals had their insoluble fractions isolated and tested by Western blotting to determine which of these proteins are insoluble and, therefore, likely to be aggregating. The ability of the proteins to co-aggregate (directly interact and form common aggregate structures) was tested by systematic pairwise expression of the proteins in SH-SY5Y neuroblastoma cells, which were then examined by immunofluorescent microscopy. RESULTS Many individuals displayed multiple insoluble proteins in the brain, although not enough to imply interaction between the proteins. Cell culture analysis revealed that only a few of the proteins analyzed can consistently co-aggregate with each other: DISC1 with each of CRMP1 and TRIOBP-1. DISC1 was able to induce aggregation of full length TRIOBP-1, but not individual domains of TRIOBP-1 when they were expressed individually. CONCLUSIONS While specific proteins are capable of co-aggregating, and appear to do so in the brains of individuals with mental illness and potentially also with suicidal tendency, it is more common for such proteins to aggregate in a parallel manner, through independent mechanisms. This information aids in understanding the distribution of protein aggregates among mental illness patients and is therefore important for any future diagnostic or therapeutic approaches based on this aspect of mental illness pathology.
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Affiliation(s)
- Bobana Samardžija
- Department of Biotechnology, University of Rijeka, 51000 Rijeka, Croatia
| | - Maja Juković
- Department of Biotechnology, University of Rijeka, 51000 Rijeka, Croatia
| | - Beti Zaharija
- Department of Biotechnology, University of Rijeka, 51000 Rijeka, Croatia
| | - Éva Renner
- Human Brain Tissue Bank & Laboratory, Semmelweis University, 1094 Budapest, Hungary
| | - Miklós Palkovits
- Human Brain Tissue Bank & Laboratory, Semmelweis University, 1094 Budapest, Hungary
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van den Oord EJCG, Xie LY, Zhao M, Campbell TL, Turecki G, Kähler AK, Dean B, Mors O, Hultman CM, Staunstrup NH, Aberg KA. Genes implicated by a methylome-wide schizophrenia study in neonatal blood show differential expression in adult brain samples. Mol Psychiatry 2023; 28:2088-2094. [PMID: 37106120 DOI: 10.1038/s41380-023-02080-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 04/13/2023] [Accepted: 04/17/2023] [Indexed: 04/29/2023]
Abstract
Schizophrenia is a disabling disorder involving genetic predisposition in combination with environmental influences that likely act via dynamic alterations of the epigenome and the transcriptome but its detailed pathophysiology is largely unknown. We performed cell-type specific methylome-wide association study of neonatal blood (N = 333) from individuals who later in life developed schizophrenia and controls. Suggestively significant associations (P < 1.0 × 10-6) were detected in all cell-types and in whole blood with methylome-wide significant associations in monocytes (P = 2.85 × 10-9-4.87 × 10-9), natural killer cells (P = 1.72 × 10-9-7.82 × 10-9) and B cells (P = 3.8 × 10-9). Validation of methylation findings in post-mortem brains (N = 596) from independent schizophrenia cases and controls showed significant enrichment of transcriptional differences (enrichment ratio = 1.98-3.23, P = 2.3 × 10-3-1.0 × 10-5), with specific highly significant differential expression for, for example, BDNF (t = -6.11, P = 1.90 × 10-9). In addition, expression difference in brain significantly predicted schizophrenia (multiple correlation = 0.15-0.22, P = 3.6 × 10-4-4.5 × 10-8). In summary, using a unique design combining pre-disease onset (neonatal) blood methylomic data and post-disease onset (post-mortem) brain transcriptional data, we have identified genes of likely functional relevance that are associated with schizophrenia susceptibility, rather than confounding disease associated artifacts. The identified loci may be of clinical value as a methylation-based biomarker for early detection of increased schizophrenia susceptibility.
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Affiliation(s)
- Edwin J C G van den Oord
- Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Lin Y Xie
- Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Min Zhao
- Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Thomas L Campbell
- Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Gustavo Turecki
- Douglas Mental Health University Institute and McGill University, Montréal, Québec, Canada
| | - Anna K Kähler
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Brian Dean
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
| | - Ole Mors
- iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
- Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Risskov, Denmark
- Center for Genomics and Personalized Medicine, University of Aarhus, Aarhus, Denmark
| | - Christina M Hultman
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Nicklas H Staunstrup
- iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
- Center for Genomics and Personalized Medicine, University of Aarhus, Aarhus, Denmark
- Department of Biomedicine, University of Aarhus, Aarhus C, Denmark
| | - Karolina A Aberg
- Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA, USA.
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Yang T, Zhang Y, Chen L, Thomas ER, Yu W, Cheng B, Li X. The potential roles of ATF family in the treatment of Alzheimer's disease. Biomed Pharmacother 2023; 161:114544. [PMID: 36934558 DOI: 10.1016/j.biopha.2023.114544] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/07/2023] [Accepted: 03/14/2023] [Indexed: 03/20/2023] Open
Abstract
Activating transcription factors, ATFs, is a family of transcription factors that activate gene expression and transcription by recognizing and combining the cAMP response element binding proteins (CREB). It is present in various viruses as a cellular gene promoter. ATFs is involved in regulating the mammalian gene expression that is associated with various cell physiological processes. Therefore, ATFs play an important role in maintaining the intracellular homeostasis. ATF2 and ATF3 is mostly involved in mediating stress responses. ATF4 regulates the oxidative metabolism, which is associated with the survival of cells. ATF5 is presumed to regulate apoptosis, and ATF6 is involved in the regulation of endoplasmic reticulum stress (ERS). ATFs is actively studied in oncology. At present, there has been an increasing amount of research on ATFs for the treatment of neurological diseases. Here, we have focused on the different types of ATFs and their association with Alzheimer's disease (AD). The level of expression of different ATFs have a significant difference in AD patients when compared to healthy control. Recent studies have suggested that ATFs are implicated in the pathogenesis of AD, such as neuronal repair, maintenance of synaptic activity, maintenance of cell survival, inhibition of apoptosis, and regulation of stress responses. In this review, the potential role of ATFs for the treatment of AD has been highlighted. In addition, we have systematically reviewed the progress of research on ATFs in AD. This review will provide a basic and innovative understanding on the pathogenesis and treatment of AD.
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Affiliation(s)
- Ting Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southwest Medical University, Luzhou 646000, China
| | - Yuhong Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southwest Medical University, Luzhou 646000, China
| | - Lixuan Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southwest Medical University, Luzhou 646000, China
| | | | - Wenjing Yu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southwest Medical University, Luzhou 646000, China
| | - Bo Cheng
- Department of Urology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Sichuan Clinical Research Center for Nephropathy, Luzhou 646000, China.
| | - Xiang Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southwest Medical University, Luzhou 646000, China.
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10
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Yaghoubzad-Maleki M, Habibi S, Heshmati E, Khalifeh K. Bioinformatics and Molecular Dynamics Studies on the Human DISC1 in Complex with the Ndel1. JOURNAL OF COMPUTATIONAL BIOPHYSICS AND CHEMISTRY 2023; 22:147-156. [DOI: 10.1142/s2737416523500084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Abstract
In this study we analyzed the sequence and structure of the human DISC1-Ndel1 complex using bioinformatics tools and molecular dynamics simulation studies. Multiple sequence alignment between the homologue protein sequences in primates shows that corresponding positions of residues in Ndel1 are highly conserved, while the DISC1 has variable conservation lines demonstrating its tolerability against various mutations during evolutionary time scale. In comparison with the mouse variant, structural analysis has shown that the evolutionary inserted charged residues in the human DISC1 (E[Formula: see text]-R[Formula: see text]) can establish intra-chain electrostatic interactions with the K[Formula: see text]-E[Formula: see text] dipeptide that may result in more stability of the DISC1 chain. According to MD simulation studies, the compactness for the human variant of the DISC1-Ndel1 is considerably lower than that of the mouse variant. Analysis of structural fluctuation shows that a fragment at the N-terminus side of the human DISC1 has more residual fluctuation. However, the Ndel1 chain of the human variant has globally more flexibility compared with the mouse variant. Considering the identical amino acid sequence of the Ndel1 chains of human and mouse, it concluded that there is a competition between the inter-chain and intra-chain electrostatic interaction in the human DISC1 that directs the complex to weaker inter-chain interactions with the expense of strengthening the intra-chain stabilizing interaction in complex.
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Affiliation(s)
| | - Saba Habibi
- Department of Biology, Faculty of Sciences, University of Zanjan, Zanjan, Iran
| | - Emran Heshmati
- Department of Biology, Faculty of Sciences, University of Zanjan, Zanjan, Iran
| | - Khosrow Khalifeh
- Department of Biology, Faculty of Sciences, University of Zanjan, Zanjan, Iran
- Department of Biotechnology, Research Institute of Modern Biological Techniques, University of Zanjan, Zanjan, Iran
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11
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Targeting Transcription Factors ATF5, CEBPB and CEBPD with Cell-Penetrating Peptides to Treat Brain and Other Cancers. Cells 2023; 12:cells12040581. [PMID: 36831248 PMCID: PMC9954556 DOI: 10.3390/cells12040581] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/08/2023] [Accepted: 02/09/2023] [Indexed: 02/16/2023] Open
Abstract
Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we recount the evidence identifying the basic leucine zipper transcription factors ATF5, CEBPB, and CEBPD as targets for brain and other malignancies. We describe strategies that exploit the structures of the three factors to create inhibitory dominant-negative (DN) mutant forms that selectively suppress growth and survival of cancer cells. We then discuss and compare four peptides (CP-DN-ATF5, Dpep, Bpep and ST101) in which DN sequences are joined with cell-penetrating domains to create drugs that pass through tissue barriers and into cells. The peptide drugs show both efficacy and safety in suppressing growth and in the survival of brain and other cancers in vivo, and ST101 is currently in clinical trials for solid tumors, including GBM. We further consider known mechanisms by which the peptides act and how these have been exploited in rationally designed combination therapies. We additionally discuss lacunae in our knowledge about the peptides that merit further research. Finally, we suggest both short- and long-term directions for creating new generations of drugs targeting ATF5, CEBPB, CEBPD, and other transcription factors for treating brain and other malignancies.
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12
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Dysregulated Signaling at Postsynaptic Density: A Systematic Review and Translational Appraisal for the Pathophysiology, Clinics, and Antipsychotics' Treatment of Schizophrenia. Cells 2023; 12:cells12040574. [PMID: 36831241 PMCID: PMC9954794 DOI: 10.3390/cells12040574] [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: 11/30/2022] [Revised: 02/07/2023] [Accepted: 02/08/2023] [Indexed: 02/12/2023] Open
Abstract
Emerging evidence from genomics, post-mortem, and preclinical studies point to a potential dysregulation of molecular signaling at postsynaptic density (PSD) in schizophrenia pathophysiology. The PSD that identifies the archetypal asymmetric synapse is a structure of approximately 300 nm in diameter, localized behind the neuronal membrane in the glutamatergic synapse, and constituted by more than 1000 proteins, including receptors, adaptors, kinases, and scaffold proteins. Furthermore, using FASS (fluorescence-activated synaptosome sorting) techniques, glutamatergic synaptosomes were isolated at around 70 nm, where the receptors anchored to the PSD proteins can diffuse laterally along the PSD and were stabilized by scaffold proteins in nanodomains of 50-80 nm at a distance of 20-40 nm creating "nanocolumns" within the synaptic button. In this context, PSD was envisioned as a multimodal hub integrating multiple signaling-related intracellular functions. Dysfunctions of glutamate signaling have been postulated in schizophrenia, starting from the glutamate receptor's interaction with scaffolding proteins involved in the N-methyl-D-aspartate receptor (NMDAR). Despite the emerging role of PSD proteins in behavioral disorders, there is currently no systematic review that integrates preclinical and clinical findings addressing dysregulated PSD signaling and translational implications for antipsychotic treatment in the aberrant postsynaptic function context. Here we reviewed a critical appraisal of the role of dysregulated PSD proteins signaling in the pathophysiology of schizophrenia, discussing how antipsychotics may affect PSD structures and synaptic plasticity in brain regions relevant to psychosis.
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13
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Eachus H, Ryu S, Placzek M, Wood J. Zebrafish as a model to investigate the CRH axis and interactions with DISC1. CURRENT OPINION IN ENDOCRINE AND METABOLIC RESEARCH 2022; 26:100383. [PMID: 36632608 PMCID: PMC9823094 DOI: 10.1016/j.coemr.2022.100383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Release of corticotropin-releasing hormone (CRH) from CRH neurons activates the hypothalamo-pituitary-adrenal (HPA) axis, one of the main physiological stress response systems. Complex feedback loops operate in the HPA axis and understanding the neurobiological mechanisms regulating CRH neurons is of great importance in the context of stress disorders. In this article, we review how in vivo studies in zebrafish have advanced knowledge of the neurobiology of CRH neurons. Disrupted-in-schizophrenia 1 (DISC1) mutant zebrafish have blunted stress responses and can be used to model human stress disorders. We propose that DISC1 influences the development and functioning of CRH neurons as a mechanism linking DISC1 to psychiatric disorders.
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Affiliation(s)
- Helen Eachus
- Living Systems Institute and College of Medicine and Health, University of Exeter, Exeter, United Kingdom
| | - Soojin Ryu
- Living Systems Institute and College of Medicine and Health, University of Exeter, Exeter, United Kingdom
- Institute of Human Genetics, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Marysia Placzek
- School of Biosciences and Bateson Centre, University of Sheffield, Sheffield, United Kingdom
| | - Jonathan Wood
- Sheffield Institute for Translational Neuroscience and Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom
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14
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Kumar U. Co-immunolocalization of Disc1 and Gas7 protein in adult mice brain. BRAIN SCIENCE ADVANCES 2022. [DOI: 10.26599/bsa.2022.9050010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Objective: The aim of the present study was to check the potential interaction of two neurodevelopmental proteins, Disc1 and Gas7, in the adult mice brain. Methods: Twenty-four male Swiss albino mice were used for the study. The mice were 12 weeks old in the beginning of the experiment. Immunohistochemistry and co-immunofluorescence were performed on the coronal sections of mice brain and immunoblotting and co-immunoprecipitation were done on the whole brain lysate. Results: Data from immunohistochemistry and co-immunofluorescence indicate the occurrence and co-localization of Disc1 and Gas7 proteins in soma and projections of the brain cells. Immunostaining was observed in cerebral cortex, hypothalamus, midbrain, pons, medulla oblongata and CA3 of hippocampus of the brain. The data from Immunoblotting and co-immunoprecipitation validates the presence and interaction of Disc1 and Gas7 protein in whole brain lysate. Conclusion: Data indicates the potential interaction of Disc1 and Gas7 protein in adult brain. The study highlights the need for further research on Disc1–Gas7 protein interaction in brain development and neuro-disorders.
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Affiliation(s)
- Udaya Kumar
- Unit of Biochemistry, Department of Zoology, University of Madras, Chennai, Tamil Nadu, India
- Department of Neurology, University of California Los Angeles, Los Angeles, California, U.S.A
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15
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Garrott SR, Gillies JP, DeSantis ME. Nde1 and Ndel1: Outstanding Mysteries in Dynein-Mediated Transport. Front Cell Dev Biol 2022; 10:871935. [PMID: 35493069 PMCID: PMC9041303 DOI: 10.3389/fcell.2022.871935] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 03/17/2022] [Indexed: 11/17/2022] Open
Abstract
Cytoplasmic dynein-1 (dynein) is the primary microtubule minus-end directed molecular motor in most eukaryotes. As such, dynein has a broad array of functions that range from driving retrograde-directed cargo trafficking to forming and focusing the mitotic spindle. Dynein does not function in isolation. Instead, a network of regulatory proteins mediate dynein’s interaction with cargo and modulate dynein’s ability to engage with and move on the microtubule track. A flurry of research over the past decade has revealed the function and mechanism of many of dynein’s regulators, including Lis1, dynactin, and a family of proteins called activating adaptors. However, the mechanistic details of two of dynein’s important binding partners, the paralogs Nde1 and Ndel1, have remained elusive. While genetic studies have firmly established Nde1/Ndel1 as players in the dynein transport pathway, the nature of how they regulate dynein activity is unknown. In this review, we will compare Ndel1 and Nde1 with a focus on discerning if the proteins are functionally redundant, outline the data that places Nde1/Ndel1 in the dynein transport pathway, and explore the literature supporting and opposing the predominant hypothesis about Nde1/Ndel1’s molecular effect on dynein activity.
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Affiliation(s)
- Sharon R. Garrott
- Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, United States
- Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, United States
| | - John P. Gillies
- Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, United States
| | - Morgan E. DeSantis
- Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, United States
- Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, United States
- *Correspondence: Morgan E. DeSantis,
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16
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What Can We Learn from Animal Models to Study Schizophrenia? ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1400:15-33. [DOI: 10.1007/978-3-030-97182-3_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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17
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Mutations in DISC1 alter IP 3R and voltage-gated Ca 2+ channel functioning, implications for major mental illness. Neuronal Signal 2021; 5:NS20180122. [PMID: 34956649 PMCID: PMC8663806 DOI: 10.1042/ns20180122] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 10/26/2021] [Accepted: 11/08/2021] [Indexed: 12/16/2022] Open
Abstract
Disrupted in Schizophrenia 1 (DISC1) participates in a wide variety of
developmental processes of central neurons. It also serves critical roles that
underlie cognitive functioning in adult central neurons. Here we summarize
DISC1’s general properties and discuss its use as a model system for
understanding major mental illnesses (MMIs). We then discuss the cellular
actions of DISC1 that involve or regulate Ca2+ signaling in adult
central neurons. In particular, we focus on the tethering role DISC1 plays in
transporting RNA particles containing Ca2+ channel subunit RNAs,
including IP3R1, CACNA1C and CACNA2D1, and in transporting mitochondria into
dendritic and axonal processes. We also review DISC1’s role in modulating
IP3R1 activity within mitochondria-associated ER membrane (MAM).
Finally, we discuss DISC1-glycogen synthase kinase 3β (GSK3β)
signaling that regulates functional expression of voltage-gated Ca2+
channels (VGCCs) at central synapses. In each case, DISC1 regulates the movement
of molecules that impact Ca2+ signaling in neurons.
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18
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Florentinus-Mefailoski A, Bowden P, Scheltens P, Killestein J, Teunissen C, Marshall JG. The plasma peptides of Alzheimer's disease. Clin Proteomics 2021; 18:17. [PMID: 34182925 PMCID: PMC8240224 DOI: 10.1186/s12014-021-09320-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 04/20/2021] [Indexed: 02/06/2023] Open
Abstract
Background A practical strategy to discover proteins specific to Alzheimer’s dementia (AD) may be to compare the plasma peptides and proteins from patients with dementia to normal controls and patients with neurological conditions like multiple sclerosis or other diseases. The aim was a proof of principle for a method to discover proteins and/or peptides of plasma that show greater observation frequency and/or precursor intensity in AD. The endogenous tryptic peptides of Alzheimer’s were compared to normals, multiple sclerosis, ovarian cancer, breast cancer, female normal, sepsis, ICU Control, heart attack, along with their institution-matched controls, and normal samples collected directly onto ice. Methods Endogenous tryptic peptides were extracted from blinded, individual AD and control EDTA plasma samples in a step gradient of acetonitrile for random and independent sampling by LC–ESI–MS/MS with a set of robust and sensitive linear quadrupole ion traps. The MS/MS spectra were fit to fully tryptic peptides within proteins identified using the X!TANDEM algorithm. Observation frequency of the identified proteins was counted using SEQUEST algorithm. The proteins with apparently increased observation frequency in AD versus AD Control were revealed graphically and subsequently tested by Chi Square analysis. The proteins specific to AD plasma by Chi Square with FDR correction were analyzed by the STRING algorithm. The average protein or peptide log10 precursor intensity was compared across disease and control treatments by ANOVA in the R statistical system. Results Peptides and/or phosphopeptides of common plasma proteins such as complement C2, C7, and C1QBP among others showed increased observation frequency by Chi Square and/or precursor intensity in AD. Cellular gene symbols with large Chi Square values (χ2 ≥ 25, p ≤ 0.001) from tryptic peptides included KIF12, DISC1, OR8B12, ZC3H12A, TNF, TBC1D8B, GALNT3, EME2, CD1B, BAG1, CPSF2, MMP15, DNAJC2, PHACTR4, OR8B3, GCK, EXOSC7, HMGA1 and NT5C3A among others. Similarly, increased frequency of tryptic phosphopeptides were observed from MOK, SMIM19, NXNL1, SLC24A2, Nbla10317, AHRR, C10orf90, MAEA, SRSF8, TBATA, TNIK, UBE2G1, PDE4C, PCGF2, KIR3DP1, TJP2, CPNE8, and NGF amongst others. STRING analysis showed an increase in cytoplasmic proteins and proteins associated with alternate splicing, exocytosis of luminal proteins, and proteins involved in the regulation of the cell cycle, mitochondrial functions or metabolism and apoptosis. Increases in mean precursor intensity of peptides from common plasma proteins such as DISC1, EXOSC5, UBE2G1, SMIM19, NXNL1, PANO, EIF4G1, KIR3DP1, MED25, MGRN1, OR8B3, MGC24039, POLR1A, SYTL4, RNF111, IREB2, ANKMY2, SGKL, SLC25A5, CHMP3 among others were associated with AD. Tryptic peptides from the highly conserved C-terminus of DISC1 within the sequence MPGGGPQGAPAAAGGGGVSHRAGSRDCLPPAACFR and ARQCGLDSR showed a higher frequency and highest intensity in AD compared to all other disease and controls. Conclusion Proteins apparently expressed in the brain that were directly related to Alzheimer’s including Nerve Growth Factor (NFG), Sphingomyelin Phosphodiesterase, Disrupted in Schizophrenia 1 (DISC1), the cell death regulator retinitis pigmentosa (NXNl1) that governs the loss of nerve cells in the retina and the cell death regulator ZC3H12A showed much higher observation frequency in AD plasma vs the matched control. There was a striking agreement between the proteins known to be mutated or dis-regulated in the brains of AD patients with the proteins observed in the plasma of AD patients from endogenous peptides including NBN, BAG1, NOX1, PDCD5, SGK3, UBE2G1, SMPD3 neuronal proteins associated with synapse function such as KSYTL4, VTI1B and brain specific proteins such as TBATA. Supplementary Information The online version contains supplementary material available at 10.1186/s12014-021-09320-2.
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Affiliation(s)
- Angelique Florentinus-Mefailoski
- Ryerson Analytical Biochemistry Laboratory (RABL), Department of Chemistry and Biology, Faculty of Science, Ryerson University, 350 Victoria St., Toronto, ON, Canada
| | - Peter Bowden
- Ryerson Analytical Biochemistry Laboratory (RABL), Department of Chemistry and Biology, Faculty of Science, Ryerson University, 350 Victoria St., Toronto, ON, Canada
| | - Philip Scheltens
- Alzheimer Center, Dept of Neurology, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - Joep Killestein
- MS Center, Dept of Neurology, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - Charlotte Teunissen
- Neurochemistry Lab and Biobank, Dept of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - John G Marshall
- Ryerson Analytical Biochemistry Laboratory (RABL), Department of Chemistry and Biology, Faculty of Science, Ryerson University, 350 Victoria St., Toronto, ON, Canada. .,International Biobank of Luxembourg (IBBL), Luxembourg Institute of Health (Formerly CRP Sante Luxembourg), Strassen, Luxembourg.
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19
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Cuveillier C, Boulan B, Ravanello C, Denarier E, Deloulme JC, Gory-Fauré S, Delphin C, Bosc C, Arnal I, Andrieux A. Beyond Neuronal Microtubule Stabilization: MAP6 and CRMPS, Two Converging Stories. Front Mol Neurosci 2021; 14:665693. [PMID: 34025352 PMCID: PMC8131560 DOI: 10.3389/fnmol.2021.665693] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 04/09/2021] [Indexed: 12/21/2022] Open
Abstract
The development and function of the central nervous system rely on the microtubule (MT) and actin cytoskeletons and their respective effectors. Although the structural role of the cytoskeleton has long been acknowledged in neuronal morphology and activity, it was recently recognized to play the role of a signaling platform. Following this recognition, research into Microtubule Associated Proteins (MAPs) diversified. Indeed, historically, structural MAPs—including MAP1B, MAP2, Tau, and MAP6 (also known as STOP);—were identified and described as MT-binding and -stabilizing proteins. Extensive data obtained over the last 20 years indicated that these structural MAPs could also contribute to a variety of other molecular roles. Among multi-role MAPs, MAP6 provides a striking example illustrating the diverse molecular and cellular properties of MAPs and showing how their functional versatility contributes to the central nervous system. In this review, in addition to MAP6’s effect on microtubules, we describe its impact on the actin cytoskeleton, on neuroreceptor homeostasis, and its involvement in signaling pathways governing neuron development and maturation. We also discuss its roles in synaptic plasticity, brain connectivity, and cognitive abilities, as well as the potential relationships between the integrated brain functions of MAP6 and its molecular activities. In parallel, the Collapsin Response Mediator Proteins (CRMPs) are presented as examples of how other proteins, not initially identified as MAPs, fall into the broader MAP family. These proteins bind MTs as well as exhibiting molecular and cellular properties very similar to MAP6. Finally, we briefly summarize the multiple similarities between other classical structural MAPs and MAP6 or CRMPs.In summary, this review revisits the molecular properties and the cellular and neuronal roles of the classical MAPs, broadening our definition of what constitutes a MAP.
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20
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Identifying Infliximab- (IFX-) Responsive Blood Signatures for the Treatment of Rheumatoid Arthritis. BIOMED RESEARCH INTERNATIONAL 2021. [DOI: 10.1155/2021/5556784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Rheumatoid arthritis (RA) is a severe chronic pathogenic inflammatory abnormality that damages small joints. Comprehensive diagnosis and treatment procedures for RA have been established because of its severe symptoms and relatively high morbidity. Medication and surgery are the two major therapeutic approaches. Infliximab (IFX) is a novel biological agent applied for the treatment of RA. IFX improves physical functions and benefits the achievement of clinical remission even under discontinuous medication. However, not all patients react to IFX, and distinguishing IFX-sensitive and IFX-resistant patients is quite difficult. Thus, how to predict the therapeutic effects of IFX on patients with RA is one of the urgent translational medicine problems in the clinical treatment of RA. In this study, we present a novel computational method for the identification of the applicable and substantial blood gene signatures of IFX sensitivity by liquid biopsy, which may assist in the establishment of a clinical drug sensitivity test standard for RA and contribute to the revelation of unique IFX-associated pharmacological mechanisms.
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21
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Wang X, Ye F, Wen Z, Guo Z, Yu C, Huang WK, Rojas Ringeling F, Su Y, Zheng W, Zhou G, Christian KM, Song H, Zhang M, Ming GL. Structural interaction between DISC1 and ATF4 underlying transcriptional and synaptic dysregulation in an iPSC model of mental disorders. Mol Psychiatry 2021; 26:1346-1360. [PMID: 31444471 PMCID: PMC8444148 DOI: 10.1038/s41380-019-0485-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 04/01/2019] [Accepted: 05/17/2019] [Indexed: 01/01/2023]
Abstract
Psychiatric disorders are a collection of heterogeneous mental disorders arising from a contribution of genetic and environmental insults, many of which molecularly converge on transcriptional dysregulation, resulting in altered synaptic functions. The underlying mechanisms linking the genetic lesion and functional phenotypes remain largely unknown. Patient iPSC-derived neurons with a rare frameshift DISC1 (Disrupted-in-schizophrenia 1) mutation have previously been shown to exhibit aberrant gene expression and deficits in synaptic functions. How DISC1 regulates gene expression is largely unknown. Here we show that Activating Transcription Factor 4 (ATF4), a DISC1 binding partner, is more abundant in the nucleus of DISC1 mutant human neurons and exhibits enhanced binding to a collection of dysregulated genes. Functionally, overexpressing ATF4 in control neurons recapitulates deficits seen in DISC1 mutant neurons, whereas transcriptional and synaptic deficits are rescued in DISC1 mutant neurons with CRISPR-mediated heterozygous ATF4 knockout. By solving the high-resolution atomic structure of the DISC1-ATF4 complex, we show that mechanistically, the mutation of DISC1 disrupts normal DISC1-ATF4 interaction, and results in excessive ATF4 binding to DNA targets and deregulated gene expression. Together, our study identifies the molecular and structural basis of an DISC1-ATF4 interaction underlying transcriptional and synaptic dysregulation in an iPSC model of mental disorders.
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Affiliation(s)
- Xinyuan Wang
- School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Fei Ye
- Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
- Center of Systems Biology and Human Health, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
| | - Zhexing Wen
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Ziyuan Guo
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Chuan Yu
- Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
| | - Wei-Kai Huang
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Pathology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Francisca Rojas Ringeling
- The Human Genetics Pre-doctoral Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Yijing Su
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Wei Zheng
- National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Guomin Zhou
- School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China
| | - Kimberly M Christian
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Hongjun Song
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Department of Cell and Developmental Biology, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Institute for Regenerative Medicine, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- The Epigenetics Institute, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
| | - Mingjie Zhang
- Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
- Center of Systems Biology and Human Health, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
| | - Guo-Li Ming
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Department of Cell and Developmental Biology, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Institute for Regenerative Medicine, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Department of Psychiatry, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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22
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Gory-Fauré S, Powell R, Jonckheere J, Lanté F, Denarier E, Peris L, Nguyen CH, Buisson A, Lafanechère L, Andrieux A. Pyr1-Mediated Pharmacological Inhibition of LIM Kinase Restores Synaptic Plasticity and Normal Behavior in a Mouse Model of Schizophrenia. Front Pharmacol 2021; 12:627995. [PMID: 33790791 PMCID: PMC8006432 DOI: 10.3389/fphar.2021.627995] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 02/04/2021] [Indexed: 12/14/2022] Open
Abstract
The search for effective treatments for neuropsychiatric disorders is ongoing, with progress being made as brain structure and neuronal function become clearer. The central roles played by microtubules (MT) and actin in synaptic transmission and plasticity suggest that the cytoskeleton and its modulators could be relevant targets for the development of new molecules to treat psychiatric diseases. In this context, LIM Kinase - which regulates both the actin and MT cytoskeleton especially in dendritic spines, the post-synaptic compartment of the synapse - might be a good target. In this study, we analyzed the consequences of blocking LIMK1 pharmacologically using Pyr1. We investigated synaptic plasticity defects and behavioral disorders in MAP6 KO mice, an animal model useful for the study of psychiatric disorders, particularly schizophrenia. Our results show that Pyr1 can modulate MT dynamics in neurons. In MAP6 KO mice, chronic LIMK inhibition by long-term treatment with Pyr1 can restore normal dendritic spine density and also improves long-term potentiation, both of which are altered in these mice. Pyr1 treatment improved synaptic plasticity, and also reduced social withdrawal and depressive/anxiety-like behavior in MAP6 KO mice. Overall, the results of this study validate the hypothesis that modulation of LIMK activity could represent a new therapeutic strategy for neuropsychiatric diseases.
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Affiliation(s)
- Sylvie Gory-Fauré
- Department of Molecular and Cellular Neurosciences, Grenoble Institute Neuroscience, Inserm U1216, Grenoble, France.,Université Grenoble Alpes, Grenoble, France
| | - Rebecca Powell
- Department of Molecular and Cellular Neurosciences, Grenoble Institute Neuroscience, Inserm U1216, Grenoble, France.,Université Grenoble Alpes, Grenoble, France
| | - Julie Jonckheere
- Department of Molecular and Cellular Neurosciences, Grenoble Institute Neuroscience, Inserm U1216, Grenoble, France.,Université Grenoble Alpes, Grenoble, France
| | - Fabien Lanté
- Department of Molecular and Cellular Neurosciences, Grenoble Institute Neuroscience, Inserm U1216, Grenoble, France.,Université Grenoble Alpes, Grenoble, France
| | - Eric Denarier
- Department of Molecular and Cellular Neurosciences, Grenoble Institute Neuroscience, Inserm U1216, Grenoble, France.,Université Grenoble Alpes, Grenoble, France.,Health Department, Interdisciplinary Research Institute of Grenoble, CEA, Grenoble, France
| | - Leticia Peris
- Department of Molecular and Cellular Neurosciences, Grenoble Institute Neuroscience, Inserm U1216, Grenoble, France.,Université Grenoble Alpes, Grenoble, France
| | - Chi Hung Nguyen
- Chimie et Modélisation pour la Biologie du Cancer, Institut Curie, PSL Research University, CNRS UMR9187, Inserm U1196, Orsay, France
| | - Alain Buisson
- Department of Molecular and Cellular Neurosciences, Grenoble Institute Neuroscience, Inserm U1216, Grenoble, France.,Université Grenoble Alpes, Grenoble, France
| | - Laurence Lafanechère
- Université Grenoble Alpes, Grenoble, France.,Microenvironment, Cell Plasticity and Signaling Department, Institute for Advanced Biosciences, CNRS UMR5309, Inserm U1209, Grenoble, France
| | - Annie Andrieux
- Department of Molecular and Cellular Neurosciences, Grenoble Institute Neuroscience, Inserm U1216, Grenoble, France.,Université Grenoble Alpes, Grenoble, France.,Health Department, Interdisciplinary Research Institute of Grenoble, CEA, Grenoble, France
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Principal Postulates of Centrosomal Biology. Version 2020. Cells 2020; 9:cells9102156. [PMID: 32987651 PMCID: PMC7598677 DOI: 10.3390/cells9102156] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 09/10/2020] [Accepted: 09/21/2020] [Indexed: 12/13/2022] Open
Abstract
The centrosome, which consists of two centrioles surrounded by pericentriolar material, is a unique structure that has retained its main features in organisms of various taxonomic groups from unicellular algae to mammals over one billion years of evolution. In addition to the most noticeable function of organizing the microtubule system in mitosis and interphase, the centrosome performs many other cell functions. In particular, centrioles are the basis for the formation of sensitive primary cilia and motile cilia and flagella. Another principal function of centrosomes is the concentration in one place of regulatory proteins responsible for the cell's progression along the cell cycle. Despite the existing exceptions, the functioning of the centrosome is subject to general principles, which are discussed in this review.
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24
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Barnett BR, Fathi F, Falco Cobra P, Yi SY, Anderson JM, Eghbalnia HR, Markley JL, Yu JPJ. Metabolic Changes in Synaptosomes in an Animal Model of Schizophrenia Revealed by 1H and 1H, 13C NMR Spectroscopy. Metabolites 2020; 10:E79. [PMID: 32102223 PMCID: PMC7074231 DOI: 10.3390/metabo10020079] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 01/31/2020] [Accepted: 02/22/2020] [Indexed: 12/15/2022] Open
Abstract
Synaptosomes are isolated nerve terminals that contain synaptic components, including neurotransmitters, metabolites, adhesion/fusion proteins, and nerve terminal receptors. The essential role of synaptosomes in neurotransmission has stimulated keen interest in understanding both their proteomic and metabolic composition. Mass spectrometric (MS) quantification of synaptosomes has illuminated their proteomic composition, but the determination of the metabolic composition by MS has been met with limited success. In this study, we report a proof-of-concept application of one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy for analyzing the metabolic composition of synaptosomes. We utilize this approach to compare the metabolic composition synaptosomes from a wild-type rat with that from a newly generated genetic rat model (Disc1 svΔ2), which qualitatively recapitulates clinically observed early DISC1 truncations associated with schizophrenia. This study demonstrates the feasibility of using NMR spectroscopy to identify and quantify metabolites within synaptosomal fractions.
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Affiliation(s)
- Brian R. Barnett
- Neuroscience Training Program, Wisconsin Institutes for Medical Research, University of Wisconsin–Madison, Madison, WI 53705, USA; (B.R.B.); (S.Y.Y.)
| | - Fariba Fathi
- Biochemistry Department, University of Wisconsin–Madison, Madison, WI 53706, USA; (F.F.); (P.F.C.); (H.R.E.); (J.L.M.)
| | - Paulo Falco Cobra
- Biochemistry Department, University of Wisconsin–Madison, Madison, WI 53706, USA; (F.F.); (P.F.C.); (H.R.E.); (J.L.M.)
| | - Sue Y. Yi
- Neuroscience Training Program, Wisconsin Institutes for Medical Research, University of Wisconsin–Madison, Madison, WI 53705, USA; (B.R.B.); (S.Y.Y.)
| | - Jacqueline M. Anderson
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA;
| | - Hamid R. Eghbalnia
- Biochemistry Department, University of Wisconsin–Madison, Madison, WI 53706, USA; (F.F.); (P.F.C.); (H.R.E.); (J.L.M.)
| | - John L. Markley
- Biochemistry Department, University of Wisconsin–Madison, Madison, WI 53706, USA; (F.F.); (P.F.C.); (H.R.E.); (J.L.M.)
| | - John-Paul J. Yu
- Neuroscience Training Program, Wisconsin Institutes for Medical Research, University of Wisconsin–Madison, Madison, WI 53705, USA; (B.R.B.); (S.Y.Y.)
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA;
- Department of Biomedical Engineering, College of Engineering, University of Wisconsin–Madison, Madison, WI 53706, USA
- Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
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25
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Evidence of association of the DISC1 interactome gene set with schizophrenia from GWAS. Prog Neuropsychopharmacol Biol Psychiatry 2019; 95:109729. [PMID: 31398428 DOI: 10.1016/j.pnpbp.2019.109729] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 07/31/2019] [Accepted: 08/03/2019] [Indexed: 12/31/2022]
Abstract
DISC1 was discovered as a gene disrupted by a balanced translocation in a large pedigree that segregated with major mental disorders, including schizophrenia. Further attempts to find genetic association with schizophrenia were inconclusive. Most of the biology of DISC1 was inferred from the functionality of its protein partners. Recently, a gene set constituted by DISC1 and several of its partners has been associated with cognitive performance during development, a well-known schizophrenia endophenotype, by means of burden test of rare disruptive variants. Here, we performed a gene set analysis using common variants from the largest schizophrenia genome-wide association study of the Psychiatric Genomics Consortium to test if this gene set is associated with schizophrenia. The main test was based on the MAGMA software. Several additional tests were performed to analyze the robustness of the main findings. The DISC1 interactome gene set was associated with schizophrenia (P = .0056), confirmed by an additional method (INRICH). This association was robust to removal of the major histocompatibility complex region, different definitions of gene boundaries, or different statistical gene models. Conditional analysis revealed that the association was not solely explained by higher expression in brain. Three genes from the gene set, CLIC1, DST, and PDE4B, were associated with schizophrenia at the gene level. Consideration of other DISC1 interactome gene sets revealed the importance of gene set definition. Therefore, we present the first evidence from genome-wide association studies of the role of DISC1 and interacting partners in schizophrenia susceptibility, reconciling genetic and molecular biology data.
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26
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Pruski M, Hu L, Yang C, Wang Y, Zhang JB, Zhang L, Huang Y, Rajnicek AM, St Clair D, McCaig CD, Lang B, Ding YQ. Roles for IFT172 and Primary Cilia in Cell Migration, Cell Division, and Neocortex Development. Front Cell Dev Biol 2019; 7:287. [PMID: 31850339 PMCID: PMC6890611 DOI: 10.3389/fcell.2019.00287] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 11/04/2019] [Indexed: 12/25/2022] Open
Abstract
The cilium of a cell translates varied extracellular cues into intracellular signals that control embryonic development and organ function. The dynamic maintenance of ciliary structure and function requires balanced bidirectional cargo transport involving intraflagellar transport (IFT) complexes. IFT172 is a member of the IFT complex B, and IFT172 mutation is associated with pathologies including short rib thoracic dysplasia, retinitis pigmentosa and Bardet-Biedl syndrome, but how it underpins these conditions is not clear. We used the WIM cell line, derived from embryonic fibroblasts of Wimple mice (carrying homozygous Leu1564Pro mutation in Ift172), to probe roles of Ift172 and primary cilia in cell behavior. WIM cells had ablated cilia and deficiencies in directed migration (electrotaxis), cell proliferation and intracellular signaling. Additionally, WIM cells displayed altered cell cycle progression, with increased numbers of chromatids, highlighting dysfunctional centrosome status. Exposure to a physiological electric field promoted a higher percentage of primary cilia in wild-type cells. Interestingly, in situ hybridization revealed an extensive and dynamic expression profile of Ift172 in both developing and adult mouse cortex. In vivo manipulation of Ift172 expression in germinal regions of embryonic mouse brains perturbed neural progenitor proliferation and radial migration of post-mitotic neurons, revealing a regulatory role of Ift172 in cerebral morphogenesis. Our data suggest that Ift172 regulates a range of fundamental biological processes, highlighting the pivotal roles of the primary cilium in cell physiology and brain development.
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Affiliation(s)
- Michal Pruski
- Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Mental Disorders, Changsha, China.,State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.,Key Laboratory of Arrhythmias, Ministry of Education, East Hospital, Department of Anatomy and Neurobiology, Collaborative Innovation Centre for Brain Science, Tongji University School of Medicine, Shanghai, China.,School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
| | - Ling Hu
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.,School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
| | - Cuiping Yang
- Key Laboratory of Arrhythmias, Ministry of Education, East Hospital, Department of Anatomy and Neurobiology, Collaborative Innovation Centre for Brain Science, Tongji University School of Medicine, Shanghai, China
| | - Yubing Wang
- Key Laboratory of Arrhythmias, Ministry of Education, East Hospital, Department of Anatomy and Neurobiology, Collaborative Innovation Centre for Brain Science, Tongji University School of Medicine, Shanghai, China
| | - Jin-Bao Zhang
- Department of Histology and Embryology, Institute of Neuroscience, Wenzhou Medical University, Wenzhou, China
| | - Lei Zhang
- Key Laboratory of Arrhythmias, Ministry of Education, East Hospital, Department of Anatomy and Neurobiology, Collaborative Innovation Centre for Brain Science, Tongji University School of Medicine, Shanghai, China.,School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
| | - Ying Huang
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.,Key Laboratory of Arrhythmias, Ministry of Education, East Hospital, Department of Anatomy and Neurobiology, Collaborative Innovation Centre for Brain Science, Tongji University School of Medicine, Shanghai, China.,School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
| | - Ann M Rajnicek
- School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
| | - David St Clair
- School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
| | - Colin D McCaig
- School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
| | - Bing Lang
- Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Mental Disorders, Changsha, China.,School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
| | - Yu-Qiang Ding
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.,Key Laboratory of Arrhythmias, Ministry of Education, East Hospital, Department of Anatomy and Neurobiology, Collaborative Innovation Centre for Brain Science, Tongji University School of Medicine, Shanghai, China
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27
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Liu CM, Liu YL, Hwu HG, Fann CSJ, Yang UC, Hsu PC, Chang CC, Chen WJ, Hwang TJ, Hsieh MH, Liu CC, Chien YL, Lin YT, Tsuang MT. Genetic associations and expression of extra-short isoforms of disrupted-in-schizophrenia 1 in a neurocognitive subgroup of schizophrenia. J Hum Genet 2019; 64:653-663. [PMID: 30976040 DOI: 10.1038/s10038-019-0597-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 03/20/2019] [Accepted: 03/21/2019] [Indexed: 01/20/2023]
Abstract
Disrupted-in-schizophrenia 1 (DISC1) was reported to be associated with schizophrenia. In a previous study, we found significant association with schizophrenia patients with deficient sustained attention assessed by continuous performance test (CPT). This study aimed to identify risk polymorphisms in this specific neurocognitive subgroup and investigate the expression of different isoforms of DISC1. A total of 83 genetic variants were identified through direct sequencing in 50 controls and 100 schizophrenia patients. Fourteen variants were genotyped in 600 controls and 912 patients. Patients were subgrouped by familial loading (multiplex or simplex) and performance on CPT. The frequency of AA genotype of rs11122324 at the 3'-UTR of Es and Esv1 isoforms and of rs2793091 at intron 4 were significantly higher in multiplex schizophrenia patients than those in controls (corrected p < 0.05). In further subgrouping, the frequency of AA genotype of the two SNPs were significantly higher in multiplex schizophrenia patients with deficient sustained attention than those in controls (corrected p < 0.005). The mRNA expression levels of two extra-short isoforms (Es and Esv1) in the EBV-transformed lymphocytes of schizophrenia were significantly higher than those of controls. Luciferase reporter assays demonstrated that the A-allele of rs11122324 significantly upregulated DISC1 extra-short isoforms transcription compared with the G-allele. We found two SNPs (rs11122324 and rs2793091) of DISC1 may be specifically associated with multiplex schizophrenia patients with deficient sustained attention. The SNP rs11122324 may be a risk polymorphism, which may have functional influence on the transcription of Es and Esv1 through increasing their expression.
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Affiliation(s)
- Chih-Min Liu
- Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. .,Neurobiology and Cognitive Science Center, National Taiwan University, Taipei, Taiwan.
| | - Yu-Li Liu
- Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan
| | - Hai-Gwo Hwu
- Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | | | - Ueng-Cheng Yang
- Institute of Bioinformatics, National Yang-Ming University, Taipei, Taiwan
| | - Pei-Chun Hsu
- Institute of Bioinformatics, National Yang-Ming University, Taipei, Taiwan
| | | | - Wei J Chen
- Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Tzung-Jeng Hwang
- Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.,Neurobiology and Cognitive Science Center, National Taiwan University, Taipei, Taiwan
| | - Ming H Hsieh
- Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chen-Chung Liu
- Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yi-Ling Chien
- Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yi-Tin Lin
- Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ming T Tsuang
- Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.,Harvard Departments of Epidemiology and Psychiatry, Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, MA, USA.,Veterans Affairs San Diego Healthcare System, San Diego, CA, USA
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28
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Wilkinson B, Evgrafov O, Zheng D, Hartel N, Knowles JA, Graham NA, Ichida J, Coba MP. Endogenous Cell Type-Specific Disrupted in Schizophrenia 1 Interactomes Reveal Protein Networks Associated With Neurodevelopmental Disorders. Biol Psychiatry 2019; 85:305-316. [PMID: 29961565 PMCID: PMC6251761 DOI: 10.1016/j.biopsych.2018.05.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 04/03/2018] [Accepted: 05/03/2018] [Indexed: 11/17/2022]
Abstract
BACKGROUND Disrupted in schizophrenia 1 (DISC1) has been implicated in a number of psychiatric diseases along with neurodevelopmental phenotypes such as the proliferation and differentiation of neural progenitor cells. While there has been significant effort directed toward understanding the function of DISC1 through the determination of its protein-protein interactions within an in vitro setting, endogenous interactions involving DISC1 within a cell type-specific setting relevant to neural development remain unclear. METHODS Using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) genome engineering technology, we inserted an endogenous 3X-FLAG tag at the C-terminus of the canonical DISC1 gene in human induced pluripotent stem cells (iPSCs). We further differentiated these cells and used affinity purification to determine protein-protein interactions involving DISC1 in iPSC-derived neural progenitor cells and astrocytes. RESULTS We were able to determine 151 novel cell type-specific proteins present in DISC1 endogenous interactomes. The DISC1 interactomes can be clustered into several subcomplexes that suggest novel DISC1 cell-specific functions. In addition, the DISC1 interactome in iPSC-derived neural progenitor cells associates in a connected network containing proteins found to harbor de novo mutations in patients affected by schizophrenia and contains a subset of novel interactions that are known to harbor syndromic mutations in neurodevelopmental disorders. CONCLUSIONS Endogenous DISC1 interactomes within iPSC-derived human neural progenitor cells and astrocytes are able to provide context to DISC1 function in a cell type-specific setting relevant to neural development and enables the integration of psychiatric disease risk factors within a set of defined molecular functions.
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Affiliation(s)
- Brent Wilkinson
- Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Oleg Evgrafov
- Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA
| | - DongQing Zheng
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90033, USA
| | - Nicolas Hartel
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90033, USA
| | - James A. Knowles
- Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA
| | - Nicholas A. Graham
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90033, USA
| | - Justin Ichida
- Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA,Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA,Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC
| | - Marcelo P. Coba
- Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA,Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA,Corresponding Author: Marcelo P. Coba, Keck School of Medicine, University of Southern California, Zilkha Neurogenetic Institute, 1501 San Pablo St, Los Angeles, CA 90033, USA. Phone: 323-442-4345.
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29
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Barnett BR, Torres-Velázquez M, Yi SY, Rowley PA, Sawin EA, Rubinstein CD, Krentz K, Anderson JM, Bakshi VP, Yu JPJ. Sex-specific deficits in neurite density and white matter integrity are associated with targeted disruption of exon 2 of the Disc1 gene in the rat. Transl Psychiatry 2019; 9:82. [PMID: 30745562 PMCID: PMC6370885 DOI: 10.1038/s41398-019-0429-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 01/24/2019] [Accepted: 01/26/2019] [Indexed: 02/06/2023] Open
Abstract
Diffusion tensor imaging (DTI) has provided remarkable insight into our understanding of white matter microstructure and brain connectivity across a broad spectrum of psychiatric disease. While DTI and other diffusion weighted magnetic resonance imaging (MRI) methods have clarified the axonal contribution to the disconnectivity seen in numerous psychiatric diseases, absent from these studies are quantitative indices of neurite density and orientation that are especially important features in regions of high synaptic density that would capture the synaptic contribution to the psychiatric disease state. Here we report the application of neurite orientation dispersion and density imaging (NODDI), an emerging microstructure imaging technique, to a novel Disc1 svΔ2 rat model of psychiatric illness and demonstrate the complementary and more specific indices of tissue microstructure found in NODDI than those reported by DTI. Our results demonstrate global and sex-specific changes in white matter microstructural integrity and deficits in neurite density as a consequence of the Disc1 svΔ2 genetic variation and highlight the application of NODDI and quantitative measures of neurite density and neurite dispersion in psychiatric disease.
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Affiliation(s)
- Brian R Barnett
- Neuroscience Training Program, Wisconsin Institutes for Medical Research, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Maribel Torres-Velázquez
- Department of Biomedical Engineering, College of Engineering, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Sue Y Yi
- Neuroscience Training Program, Wisconsin Institutes for Medical Research, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Paul A Rowley
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA
| | - Emily A Sawin
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA
| | - C Dustin Rubinstein
- Biotechnology Center, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Kathleen Krentz
- Biotechnology Center, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Jacqueline M Anderson
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA
| | - Vaishali P Bakshi
- Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA
| | - John-Paul J Yu
- Neuroscience Training Program, Wisconsin Institutes for Medical Research, University of Wisconsin-Madison, Madison, WI, 53705, USA.
- Department of Biomedical Engineering, College of Engineering, University of Wisconsin-Madison, Madison, WI, 53706, USA.
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA.
- Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA.
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30
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Shen X, Yeung HT, Lai KO. Application of Human-Induced Pluripotent Stem Cells (hiPSCs) to Study Synaptopathy of Neurodevelopmental Disorders. Dev Neurobiol 2018; 79:20-35. [PMID: 30304570 DOI: 10.1002/dneu.22644] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 09/27/2018] [Accepted: 10/04/2018] [Indexed: 12/15/2022]
Abstract
Synapses are the basic structural and functional units for information processing and storage in the brain. Their diverse properties and functions ultimately underlie the complexity of human behavior. Proper development and maintenance of synapses are essential for normal functioning of the nervous system. Disruption in synaptogenesis and the consequent alteration in synaptic function have been strongly implicated to cause neurodevelopmental disorders such as autism spectrum disorders (ASDs) and schizophrenia (SCZ). The introduction of human-induced pluripotent stem cells (hiPSCs) provides a new path to elucidate disease mechanisms and potential therapies. In this review, we will discuss the advantages and limitations of using hiPSC-derived neurons to study synaptic disorders. Many mutations in genes encoding for proteins that regulate synaptogenesis have been identified in patients with ASDs and SCZ. We use Methyl-CpG binding protein 2 (MECP2), SH3 and multiple ankyrin repeat domains 3 (SHANK3) and Disrupted in schizophrenia 1 (DISC1) as examples to illustrate the promise of using hiPSCs as cellular models to elucidate the mechanisms underlying disease-related synaptopathy.
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Affiliation(s)
- Xuting Shen
- Faculty of Medicine, School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Hong Kong, China
| | - Hoi Ting Yeung
- Faculty of Medicine, School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Hong Kong, China
| | - Kwok-On Lai
- Faculty of Medicine, School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Hong Kong, China.,State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, 21 Sassoon Road, Hong Kong, China
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31
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Weng YT, Chien T, Kuan II, Chern Y. The TRAX, DISC1, and GSK3 complex in mental disorders and therapeutic interventions. J Biomed Sci 2018; 25:71. [PMID: 30285728 PMCID: PMC6171312 DOI: 10.1186/s12929-018-0473-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 09/25/2018] [Indexed: 01/15/2023] Open
Abstract
Psychiatric disorders (such as bipolar disorder, depression, and schizophrenia) affect the lives of millions of individuals worldwide. Despite the tremendous efforts devoted to various types of psychiatric studies and rapidly accumulating genetic information, the molecular mechanisms underlying psychiatric disorder development remain elusive. Among the genes that have been implicated in schizophrenia and other mental disorders, disrupted in schizophrenia 1 (DISC1) and glycogen synthase kinase 3 (GSK3) have been intensively investigated. DISC1 binds directly to GSK3 and modulates many cellular functions by negatively inhibiting GSK3 activity. The human DISC1 gene is located on chromosome 1 and is highly associated with schizophrenia and other mental disorders. A recent study demonstrated that a neighboring gene of DISC1, translin-associated factor X (TRAX), binds to the DISC1/GSK3β complex and at least partly mediates the actions of the DISC1/GSK3β complex. Previous studies also demonstrate that TRAX and most of its interacting proteins that have been identified so far are risk genes and/or markers of mental disorders. In the present review, we will focus on the emerging roles of TRAX and its interacting proteins (including DISC1 and GSK3β) in psychiatric disorders and the potential implications for developing therapeutic interventions.
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Affiliation(s)
- Yu-Ting Weng
- Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Rd. Nankang, Taipei, 115, Taiwan, Republic of China.,Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, No.155, Sec.2, Linong Street, Taipei, 112, Taiwan, Republic of China
| | - Ting Chien
- Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Rd. Nankang, Taipei, 115, Taiwan, Republic of China
| | - I-I Kuan
- Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Rd. Nankang, Taipei, 115, Taiwan, Republic of China
| | - Yijuang Chern
- Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Rd. Nankang, Taipei, 115, Taiwan, Republic of China. .,Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, No.155, Sec.2, Linong Street, Taipei, 112, Taiwan, Republic of China.
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32
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The complexity of the cilium: spatiotemporal diversity of an ancient organelle. Curr Opin Cell Biol 2018; 55:139-149. [PMID: 30138887 DOI: 10.1016/j.ceb.2018.08.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 07/31/2018] [Accepted: 08/02/2018] [Indexed: 02/06/2023]
Abstract
Cilia are microtubule-based appendages present on almost all vertebrate cell types where they mediate a myriad of cellular processes critical for development and homeostasis. In humans, impaired ciliary function is associated with an ever-expanding repertoire of phenotypically-overlapping yet highly variable genetic disorders, the ciliopathies. Extensive work to elucidate the structure, function, and composition of the cilium is offering hints that the `static' representation of the cilium is a gross oversimplification of a highly dynamic organelle whose functions are choreographed dynamically across cell types, developmental, and homeostatic contexts. Understanding this diversity will require discerning ciliary versus non-ciliary roles for classically-defined `ciliary' proteins; defining ciliary protein-protein interaction networks within and beyond the cilium; and resolving the spatiotemporal diversity of ciliary structure and function. Here, focusing on one evolutionarily conserved ciliary module, the intraflagellar transport system, we explore these ideas and propose potential future studies that will improve our knowledge gaps of the oversimplified cilium and, by extension, inform the reasons that underscore the striking range of clinical pathologies associated with ciliary dysfunction.
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33
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Tropea D, Hardingham N, Millar K, Fox K. Mechanisms underlying the role of DISC1 in synaptic plasticity. J Physiol 2018; 596:2747-2771. [PMID: 30008190 PMCID: PMC6046077 DOI: 10.1113/jp274330] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Accepted: 02/02/2018] [Indexed: 12/11/2022] Open
Abstract
Disrupted in schizophrenia 1 (DISC1) is an important hub protein, forming multimeric complexes by self-association and interacting with a large number of synaptic and cytoskeletal molecules. The synaptic location of DISC1 in the adult brain suggests a role in synaptic plasticity, and indeed, a number of studies have discovered synaptic plasticity impairments in a variety of different DISC1 mutants. This review explores the possibility that DISC1 is an important molecule for organizing proteins involved in synaptic plasticity and examines why mutations in DISC1 impair plasticity. It concentrates on DISC1's role in interacting with synaptic proteins, controlling dendritic structure and cellular trafficking of mRNA, synaptic vesicles and mitochondria. N-terminal directed mutations appear to impair synaptic plasticity through interactions with phosphodiesterase 4B (PDE4B) and hence protein kinase A (PKA)/GluA1 and PKA/cAMP response element-binding protein (CREB) signalling pathways, and affect spine structure through interactions with kalirin 7 (Kal-7) and Rac1. C-terminal directed mutations also impair plasticity possibly through altered interactions with lissencephaly protein 1 (LIS1) and nuclear distribution protein nudE-like 1 (NDEL1), thereby affecting developmental processes such as dendritic structure and spine maturation. Many of the same molecules involved in DISC1's cytoskeletal interactions are also involved in intracellular trafficking, raising the possibility that impairments in intracellular trafficking affect cytoskeletal development and vice versa. While the multiplicity of DISC1 protein interactions makes it difficult to pinpoint a single causal signalling pathway, we suggest that the immediate-term effects of N-terminal influences on GluA1, Rac1 and CREB, coupled with the developmental effects of C-terminal influences on trafficking and the cytoskeleton make up the two main branches of DISC1's effect on synaptic plasticity and dendritic spine stability.
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Affiliation(s)
- Daniela Tropea
- Neurospychiatric GeneticsTrinity Center for Health Sciences and Trinity College Institute of Neuroscience (TCIN)Trinity College DublinDublinIreland
| | - Neil Hardingham
- School of BiosciencesMuseum AvenueCardiff UniversityCardiffUK
| | - Kirsty Millar
- Centre for Genomic & Experimental MedicineMRC Institute of Genetics & Molecular MedicineWestern General HospitalUniversity of EdinburghCrewe RoadEdinburghUK
| | - Kevin Fox
- School of BiosciencesMuseum AvenueCardiff UniversityCardiffUK
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Bradshaw NJ, Ukkola-Vuoti L, Pankakoski M, Zheutlin AB, Ortega-Alonso A, Torniainen-Holm M, Sinha V, Therman S, Paunio T, Suvisaari J, Lönnqvist J, Cannon TD, Haukka J, Hennah W. The NDE1 genomic locus can affect treatment of psychiatric illness through gene expression changes related to microRNA-484. Open Biol 2018; 7:rsob.170153. [PMID: 29142105 PMCID: PMC5717342 DOI: 10.1098/rsob.170153] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 10/09/2017] [Indexed: 01/16/2023] Open
Abstract
Genetic studies of familial schizophrenia in Finland have observed significant associations with a group of biologically related genes, DISC1, NDE1, NDEL1, PDE4B and PDE4D, the ‘DISC1 network’. Here, we use gene expression and psychoactive medication use data to study their biological consequences and potential treatment implications. Gene expression levels were determined in 64 individuals from 18 families, while prescription medication information has been collected over a 10-year period for 931 affected individuals. We demonstrate that the NDE1 SNP rs2242549 associates with significant changes in gene expression for 2908 probes (2542 genes), of which 794 probes (719 genes) were replicable. A significant number of the genes altered were predicted targets of microRNA-484 (p = 3.0 × 10−8), located on a non-coding exon of NDE1. Variants within the NDE1 locus also displayed significant genotype by gender interaction to early cessation of psychoactive medications metabolized by CYP2C19. Furthermore, we demonstrate that miR-484 can affect the expression of CYP2C19 in a cell culture system. Thus, variation at the NDE1 locus may alter risk of mental illness, in part through modification of miR-484, and such modification alters treatment response to specific psychoactive medications, leading to the potential for use of this locus in targeting treatment.
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Affiliation(s)
- Nicholas J Bradshaw
- Department of Neuropathology, Heinrich Heine University, 40225 Düsseldorf, Germany.,Department of Biotechnology, University of Rijeka, 51000 Rijeka, Croatia
| | - Liisa Ukkola-Vuoti
- Mental Health Unit, Department of Health, National Institute for Health and Welfare, 00271 Helsinki, Finland.,Institute for Molecular Medicine Finland FIMM, University of Helsinki, 00014 Helsinki, Finland.,Medicum, Clinicum, University of Helsinki, 00014 Helsinki, Finland
| | - Maiju Pankakoski
- Mental Health Unit, Department of Health, National Institute for Health and Welfare, 00271 Helsinki, Finland
| | | | - Alfredo Ortega-Alonso
- Mental Health Unit, Department of Health, National Institute for Health and Welfare, 00271 Helsinki, Finland.,Institute for Molecular Medicine Finland FIMM, University of Helsinki, 00014 Helsinki, Finland
| | - Minna Torniainen-Holm
- Mental Health Unit, Department of Health, National Institute for Health and Welfare, 00271 Helsinki, Finland.,Institute for Molecular Medicine Finland FIMM, University of Helsinki, 00014 Helsinki, Finland
| | - Vishal Sinha
- Mental Health Unit, Department of Health, National Institute for Health and Welfare, 00271 Helsinki, Finland.,Institute for Molecular Medicine Finland FIMM, University of Helsinki, 00014 Helsinki, Finland.,Medicum, Clinicum, University of Helsinki, 00014 Helsinki, Finland
| | - Sebastian Therman
- Mental Health Unit, Department of Health, National Institute for Health and Welfare, 00271 Helsinki, Finland
| | - Tiina Paunio
- Genomics and Biomarkers Unit, Department of Health, National Institute for Health and Welfare, 00271 Helsinki, Finland.,Department of Psychiatry, University of Helsinki and Helsinki University Hospital, 00014 Helsinki, Finland
| | - Jaana Suvisaari
- Mental Health Unit, Department of Health, National Institute for Health and Welfare, 00271 Helsinki, Finland
| | - Jouko Lönnqvist
- Mental Health Unit, Department of Health, National Institute for Health and Welfare, 00271 Helsinki, Finland.,Department of Psychiatry, University of Helsinki and Helsinki University Hospital, 00014 Helsinki, Finland
| | - Tyrone D Cannon
- Department of Psychology, Yale University, New Haven, CT 06520, USA
| | - Jari Haukka
- Mental Health Unit, Department of Health, National Institute for Health and Welfare, 00271 Helsinki, Finland.,Department of Public Health, Clinicum, University of Helsinki, 00014 Helsinki, Finland
| | - William Hennah
- Mental Health Unit, Department of Health, National Institute for Health and Welfare, 00271 Helsinki, Finland .,Institute for Molecular Medicine Finland FIMM, University of Helsinki, 00014 Helsinki, Finland.,Medicum, Clinicum, University of Helsinki, 00014 Helsinki, Finland
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35
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Yan L, Zhou J, Wang D, Si D, Liu Y, Zhong L, Yin Y. Unbiased lipidomic profiling reveals metabolomic changes during the onset and antipsychotics treatment of schizophrenia disease. Metabolomics 2018; 14:80. [PMID: 30830385 DOI: 10.1007/s11306-018-1375-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 05/16/2018] [Indexed: 01/22/2023]
Abstract
INTRODUCTION Schizophrenia (SCH) is one of the most common psychiatric disorders, which involves impairments in motivation and cognition. The pathological mechanisms underlying SCH are still unknown, and no effective therapies can prevent or treat perfectly the cognitive impairments and deficit symptoms caused by SCH. OBJECTIVES We aimed to find the lipid expression change in plasma that underlie SCH onset and antipsychotics treatment. METHODS We performed a data independent acquisition-based untargeted lipidomic approach on a quadrupole-time of flight liquid chromatography coupled to mass spectrometry platform. The plasma lipidomic profiles of SCH patients (n = 20) pre- and post-antipsychotics treatment were acquired as well as healthy controls (n = 29). Grouped or paired t-test were used to analyze the data. RESULTS Over 1000 features were detected by our lipidomic analysis, of which 445 lipids belonging to 17 lipid species were reliably identified by tandem mass spectrometry. After statistical analysis, 47 lipids belonging to 9 lipid species were found to be dysregulated between naive SCH patients and healthy controls, and 50 lipids belonging to 9 lipid species were found to be dysregulated after antipsychotics treatment. These findings include several new SCH-relevant lipid species such as sphingomyelin, acylcarnitine and ceramide. Four types of lipid expression regulative patterns can be concluded from the above mentioned findings, revealing information about mechanism, side-effect and potential target of antipsychotics. CONCLUSIONS The work presented here have revealed several new lipid species which are significantly dysregulated in SCH disease development or antipsychotics treatment. These lipids provide new evidence for the pathological studies of SCH and new antipsychotics development, or can be considered as potentially candidate biomarkers for further validation.
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Affiliation(s)
- Lailai Yan
- Department of Laboratorial Science and Technology, Vaccine Research Center, School of Public Health, Peking University, Beijing, 100191, China
- Medical and Health Analytical Center, Peking University Health Science Center, Beijing, 100191, China
| | - Juntuo Zhou
- Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Dongfang Wang
- Department of Laboratorial Science and Technology, Vaccine Research Center, School of Public Health, Peking University, Beijing, 100191, China
| | - Dandan Si
- AB Sciex Analytical Instrument Trading Co., Ltd, Beijing Office, Beijing, 100015, China
| | - Yaqiong Liu
- Department of Laboratorial Science and Technology, Vaccine Research Center, School of Public Health, Peking University, Beijing, 100191, China
| | - Lijun Zhong
- Medical and Health Analytical Center, Peking University Health Science Center, Beijing, 100191, China.
| | - Yuxin Yin
- Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
- Medical and Health Analytical Center, Peking University Health Science Center, Beijing, 100191, China.
- Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
- Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center for Life Sciences, Beijing, 100191, China.
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36
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Katsel P, Fam P, Tan W, Khan S, Yang C, Jouroukhin Y, Rudchenko S, Pletnikov MV, Haroutunian V. Overexpression of Truncated Human DISC1 Induces Appearance of Hindbrain Oligodendroglia in the Forebrain During Development. Schizophr Bull 2018; 44:515-524. [PMID: 28981898 PMCID: PMC5890457 DOI: 10.1093/schbul/sbx106] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Genetic, neuroimaging, and gene expression studies suggest a role for oligodendrocyte (OLG) dysfunction in schizophrenia (SZ). Disrupted-in-schizophrenia 1 (DISC1) is a risk gene for major psychiatric disorders, including SZ. Overexpression of mutant truncated (hDISC1), but not full-length sequence of human DISC1 in forebrain influenced OLG differentiation and proliferation of glial progenitors in the developing cerebral cortex concurrently with reduction of OLG progenitor markers in the hindbrain. We examined gene and protein expression of the molecular determinants of hindbrain OLG development and their interactions with DISC1 in mutant hDISC1 mice. We found ectopic upregulation of hindbrain glial progenitor markers (early growth response 2 [Egr2] and NK2 homeobox 2 [Nkx2-2]) in the forebrain of hDISC1 (E15) embryos. DISC1 and Nkx2-2 were coexpressed and interacted in progenitor cells. Overexpression of truncated hDISC1 impaired interactions between DISC1 and Nkx2-2, which was associated with increased differentiation of OLG and upregulation of hindbrain mature OLG markers (laminin alpha-1 [LAMA1] and myelin protein zero [MPZ]) suggesting a suppressive function of endogenous DISC1 in OLG specialization of hindbrain glial progenitors during embryogenesis. Consistent with findings in hDISC1 mice, several hindbrain OLG markers (PRX, LAMA1, and MPZ) were significantly upregulated in the superior temporal cortex of persons with SZ. These findings show a significant effect of truncated hDISC1 on glial identity cells along the rostrocaudal axis and their OLG specification. Appearance of hindbrain OLG lineage cells and their premature differentiation may affect cerebrocortical organization and contribute to the pathophysiology of SZ.
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Affiliation(s)
- Pavel Katsel
- Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, NY,To whom correspondence should be addressed; JJ Peters VA Medical Center, 151 Research Build, Room 5F-04C, 130 West Kingsbridge Road, Bronx, NY 10468; tel: 718-584-9000 ext. 6067, fax: 718-741-4746, e-mail:
| | - Peter Fam
- Department of Psychiatry, James J Peters VA Medical Center, Bronx, NY
| | - Weilun Tan
- Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, NY
| | - Sonia Khan
- Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, NY
| | - Chunxia Yang
- Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Yan Jouroukhin
- Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD
| | | | - Mikhail V Pletnikov
- Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Vahram Haroutunian
- Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, NY,Department of Neuroscience, The Icahn School of Medicine at Mount Sinai, New York, NY,Mental Illness Research, Education and Clinical Center (MIRECC), James J Peters VA Medical Center, Bronx, NY
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37
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Kinesin 1 regulates cilia length through an interaction with the Bardet-Biedl syndrome related protein CCDC28B. Sci Rep 2018; 8:3019. [PMID: 29445114 PMCID: PMC5813027 DOI: 10.1038/s41598-018-21329-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 02/02/2018] [Indexed: 01/12/2023] Open
Abstract
Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinal degeneration, obesity, polydactyly, renal disease and mental retardation. CCDC28B is a BBS-associated protein that we have previously shown plays a role in cilia length regulation whereby its depletion results in shortened cilia both in cells and Danio rerio (zebrafish). At least part of that role is achieved by its interaction with the mTORC2 component SIN1, but the mechanistic details of this interaction and/or additional functions that CCDC28B might play in the context of cilia remain poorly understood. Here we uncover a novel interaction between CCDC28B and the kinesin 1 molecular motor that is relevant to cilia. CCDC28B interacts with kinesin light chain 1 (KLC1) and the heavy chain KIF5B. Notably, depletion of these kinesin 1 components results in abnormally elongated cilia. Furthermore, through genetic interaction studies we demonstrate that kinesin 1 regulates ciliogenesis through CCDC28B. We show that kinesin 1 regulates the subcellular distribution of CCDC28B, unexpectedly, inhibiting its nuclear accumulation, and a ccdc28b mutant missing a nuclear localization motif fails to rescue the phenotype in zebrafish morphant embryos. Therefore, we uncover a previously unknown role of kinesin 1 in cilia length regulation that relies on the BBS related protein CCDC28B.
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38
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Pina-Camacho L, Parellada M, Kyriakopoulos M. Autism spectrum disorder and schizophrenia: boundaries and uncertainties. BJPSYCH ADVANCES 2018. [DOI: 10.1192/apt.bp.115.014720] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
SummaryAutism and schizophrenia were placed in different diagnostic categories in DSM-III, having previously been considered as related diagnostic entities. New evidence suggests that these disorders show clinical and cognitive deficit overlaps and shared neurobiological characteristics. Furthermore, children presenting with both autism spectrum disorder (ASD) and psychotic experiences may represent a subgroup of ASD more closely linked to psychosis. The study of ASD and childhood schizophrenia, and their clinical boundaries and overlapping pathophysiological characteristics, may clarify their relationship and lead to more effective interventions. This article discusses the relationship through a critical review of current and historical dilemmas surrounding the phenomenology and pathophysiology of these disorders. It provides a framework for working with children and young people with mixed clinical presentations, illustrated by three brief fictional case vignettes.
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39
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Fukuda T, Yanagi S. Psychiatric behaviors associated with cytoskeletal defects in radial neuronal migration. Cell Mol Life Sci 2017; 74:3533-3552. [PMID: 28516224 PMCID: PMC11107632 DOI: 10.1007/s00018-017-2539-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 04/21/2017] [Accepted: 05/11/2017] [Indexed: 12/17/2022]
Abstract
Normal development of the cerebral cortex is an important process for higher brain functions, such as language, and cognitive and social functions. Psychiatric disorders, such as schizophrenia and autism, are thought to develop owing to various dysfunctions occurring during the development of the cerebral cortex. Radial neuronal migration in the embryonic cerebral cortex is a complex process, which is achieved by strict control of cytoskeletal dynamics, and impairments in this process are suggested to cause various psychiatric disorders. Our recent findings indicate that radial neuronal migration as well as psychiatric behaviors is rescued by controlling microtubule stability during the embryonic stage. In this review, we outline the relationship between psychiatric disorders, such as schizophrenia and autism, and radial neuronal migration in the cerebral cortex by focusing on the cytoskeleton and centrosomes. New treatment strategies for psychiatric disorders will be discussed.
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Affiliation(s)
- Toshifumi Fukuda
- Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan.
| | - Shigeru Yanagi
- Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan.
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40
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41
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Das S, Suresh B, Kim HH, Ramakrishna S. RanBPM: a potential therapeutic target for modulating diverse physiological disorders. Drug Discov Today 2017; 22:1816-1824. [PMID: 28847759 DOI: 10.1016/j.drudis.2017.08.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 06/26/2017] [Accepted: 08/21/2017] [Indexed: 02/06/2023]
Abstract
The Ran-binding protein microtubule-organizing center (RanBPM) is a highly conserved nucleocytoplasmic protein involved in a variety of intracellular signaling pathways that control diverse cellular functions. RanBPM interacts with proteins that are linked to various diseases, including Alzheimer's disease (AD), schizophrenia (SCZ), and cancer. In this article, we define the characteristics of the scaffolding protein RanBPM and focus on its interaction partners in diverse physiological disorders, such as neurological diseases, fertility disorders, and cancer.
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Affiliation(s)
- Soumyadip Das
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, 04763, South Korea
| | - Bharathi Suresh
- Department of Pharmacology, Yonsei University College of Medicine, Seoul, 03722, South Korea.
| | - Hyongbum Henry Kim
- Department of Pharmacology, Yonsei University College of Medicine, Seoul, 03722, South Korea; Brain Korea 21 Plus Project for Medical Sciences, Yonsei University College of Medicine, Seoul, 03722, South Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 03722, South Korea; Center for Nanomedicine, Institute for Basic Science (IBS), Seoul, 03722, South Korea.
| | - Suresh Ramakrishna
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, 04763, South Korea; College of Medicine, Hanyang University, Seoul, 04763, South Korea.
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42
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Tian Y, Zhang ZC, Han J. Drosophila Studies on Autism Spectrum Disorders. Neurosci Bull 2017; 33:737-746. [PMID: 28795356 DOI: 10.1007/s12264-017-0166-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 04/23/2017] [Indexed: 02/07/2023] Open
Abstract
In the past decade, numerous genes associated with autism spectrum disorders (ASDs) have been identified. These genes encode key regulators of synaptogenesis, synaptic function, and synaptic plasticity. Drosophila is a prominent model system for ASD studies to define novel genes linked to ASDs and decipher their molecular roles in synaptogenesis, synaptic function, synaptic plasticity, and neural circuit assembly and consolidation. Here, we review Drosophila studies on ASD genes that regulate synaptogenesis, synaptic function, and synaptic plasticity through modulating chromatin remodeling, transcription, protein synthesis and degradation, cytoskeleton dynamics, and synaptic scaffolding.
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Affiliation(s)
- Yao Tian
- Institute of Life Sciences, The Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, 210096, China
| | - Zi Chao Zhang
- Institute of Life Sciences, The Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, 210096, China
| | - Junhai Han
- Institute of Life Sciences, The Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, 210096, China.
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43
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Shi L, Muthusamy N, Smith D, Bergson C. Dynein binds and stimulates axonal motility of the endosome adaptor and NEEP21 family member, calcyon. Int J Biochem Cell Biol 2017; 90:93-102. [PMID: 28734834 DOI: 10.1016/j.biocel.2017.07.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 07/11/2017] [Accepted: 07/12/2017] [Indexed: 01/31/2023]
Abstract
The neuron-enriched, endosomal protein Calcyon (Caly) regulates endocytosis and vesicle sorting, and is important for synaptic plasticity and brain development. In the current investigation of Caly interacting proteins in brain, the microtubule retrograde motor subunit, cytoplasmic dynein 1 heavy chain (DYNC1H), and microtubule structural proteins, α and β tubulin, were identified as Caly associated proteins by MALDI-ToF/ToF. Direct interaction of the Caly-C terminus with dynein and tubulin was further confirmed in in vitro studies. In Cos-7 cells, mCherry-Caly moved along the microtubule network in organelles largely labeled by the late endosome marker Rab7. Expression of the dynein inhibitor CC1, produced striking alterations in Caly distribution, consistent with retrograde motors playing a prominent role in Caly localization and movement. In axons of cultured adult rat sensory neurons, Caly-positive organelles co-localized with dynein intermediate chain (DYNC1I1-isoform IC-1B) and the dynein regulator, lissencephaly 1 (LIS1), both of which co-precipitated from brain with the Caly C-terminus. Manipulation of dynein function in axons altered the motile properties of Caly indicating that Caly vesicles utilize the retrograde motor. Altogether, the current evidence for association with dynein motors raises the possibility that the endocytic and cargo sorting functions of Caly in neurons could be regulated by interaction with the microtubule transport system.
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Affiliation(s)
- Liang Shi
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Nagendran Muthusamy
- Department of Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Deanna Smith
- Department of Biological Sciences, University of South Carolina, Columbia, SC, USA
| | - Clare Bergson
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
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44
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Bradshaw NJ. The interaction of schizophrenia-related proteins DISC1 and NDEL1, in light of the newly identified domain structure of DISC1. Commun Integr Biol 2017. [PMCID: PMC5595412 DOI: 10.1080/19420889.2017.1335375] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
DISC1 and NDEL1 are both key proteins in cortical neurodevelopment, which are each also implicated in the pathogenesis of mental illness. That the two proteins interact with each other in a functionally important manner is well established, but two distinct binding domains for NDEL1 on DISC1 have been proposed. A partial domain structure for DISC1 has recently been described, consisting of 4 structured regions referred to as “D,” “I,” “S” and “C” respectively, with one of the NDEL1 binding sites lying in the “C” region of DISC1. In light of this domain structure, it can be deduced that this site is the likely location at which NDEL1 binds, although the other proposed site (which lies in the DISC1 “I” and “S” regions) may indirectly impact on DISC1-NDEL1 interactions through determination of the oligomeric state of DISC1.
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Affiliation(s)
- Nicholas J. Bradshaw
- Department of Biotechnology, University of Rijeka, Rijeka, Croatia
- Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany
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45
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Kimura E, Kubo KI, Endo T, Nakajima K, Kakeyama M, Tohyama C. Excessive activation of AhR signaling disrupts neuronal migration in the hippocampal CA1 region in the developing mouse. J Toxicol Sci 2017; 42:25-30. [PMID: 28070106 DOI: 10.2131/jts.42.25] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
The aryl hydrocarbon receptor (AhR) avidly binds dioxin, a ubiquitous environmental contaminant. Disruption of downstream AhR signaling has been reported to alter neuronal development, and rodent offspring exposed to dioxin during gestation and lactation showed abnormalities in learning and memory, emotion, and social behavior. However, the mechanism behind the disrupted AhR signaling and developmental neurotoxicity induced by xenobiotic ligands remains elusive. Therefore, we studied how excessive AhR activation affects neuronal migration in the hippocampal CA1 region of the developing mouse brain. We transfected constitutively active (CA)-AhR, AhR, or control vector plasmids into neurons via in utero electroporation on gestational day 14 and analyzed neuronal positioning in the hippocampal CA1 region of offspring on postnatal day 14. CA-AhR transfection affected neuronal positioning, whereas no change was observed in AhR-transfected or control hippocampus. These results suggest that constitutively activated AhR signaling disrupts neuronal migration during hippocampal development. Further studies are needed to investigate whether such developmental disruption in the hippocampus leads to the abnormal cognition and behavior of rodent offspring upon maternal exposure to AhR xenobiotic ligands.
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Affiliation(s)
- Eiki Kimura
- Laboratory of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo
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Bradshaw NJ, Hayashi MAF. NDE1 and NDEL1 from genes to (mal)functions: parallel but distinct roles impacting on neurodevelopmental disorders and psychiatric illness. Cell Mol Life Sci 2017; 74:1191-1210. [PMID: 27742926 PMCID: PMC11107680 DOI: 10.1007/s00018-016-2395-7] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 09/13/2016] [Accepted: 10/06/2016] [Indexed: 01/01/2023]
Abstract
NDE1 (Nuclear Distribution Element 1, also known as NudE) and NDEL1 (NDE-Like 1, also known as NudEL) are the mammalian homologues of the fungus nudE gene, with important and at least partially overlapping roles for brain development. While a large number of studies describe the various properties and functions of these proteins, many do not directly compare the similarities and differences between NDE1 and NDEL1. Although sharing a high degree structural similarity and multiple common cellular roles, each protein presents several distinct features that justify their parallel but also unique functions. Notably both proteins have key binding partners in dynein, LIS1 and DISC1, which impact on neurodevelopmental and psychiatric illnesses. Both are implicated in schizophrenia through genetic and functional evidence, with NDE1 also strongly implicated in microcephaly, as well as other neurodevelopmental and psychiatric conditions through copy number variation, while NDEL1 possesses an oligopeptidase activity with a unique potential as a biomarker in schizophrenia. In this review, we aim to give a comprehensive overview of the various cellular roles of these proteins in a "bottom-up" manner, from their biochemistry and protein-protein interactions on the molecular level, up to the consequences for neuronal differentiation, and ultimately to their importance for correct cortical development, with direct consequences for the pathophysiology of neurodevelopmental and mental illness.
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Affiliation(s)
- Nicholas J Bradshaw
- Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany.
| | - Mirian A F Hayashi
- Department of Pharmacology, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, Brazil
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47
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Galgano D, Onnis A, Pappalardo E, Galvagni F, Acuto O, Baldari CT. The T cell IFT20 interactome reveals new players in immune synapse assembly. J Cell Sci 2017; 130:1110-1121. [PMID: 28154159 DOI: 10.1242/jcs.200006] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 01/30/2017] [Indexed: 12/17/2022] Open
Abstract
Sustained signalling at the immune synapse (IS) requires the synaptic delivery of recycling endosome-associated T cell antigen receptors (TCRs). IFT20, a component of the intraflagellar transport system, controls TCR recycling to the IS as a complex with IFT57 and IFT88. Here, we used quantitative mass spectrometry to identify additional interaction partners of IFT20 in Jurkat T cells. In addition to IFT57 and IFT88, the analysis revealed new binding partners, including IFT54 (also known as TRAF3IP1), GMAP-210 (also known as TRIP11), Arp2/3 complex subunit-3 (ARPC3), COP9 signalosome subunit-1 (CSN1, also known as GPS1) and ERGIC-53 (also known as LMAN1). A direct interaction between IFT20 and both IFT54 and GMAP-210 was confirmed in pulldown assays. Confocal imaging of antigen-specific conjugates using T cells depleted of these proteins by RNA interference showed that TCR accumulation and phosphotyrosine signalling at the IS were impaired in the absence of IFT54, ARPC3 or ERGIC-53. Similar to in IFT20-deficient T cells, this defect resulted from a reduced ability of endosomal TCRs to polarize to the IS despite a correct translocation of the centrosome towards the antigen-presenting cell contact. Our data underscore the traffic-related role of an IFT20 complex that includes components of the intracellular trafficking machinery in IS assembly.
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Affiliation(s)
- Donatella Galgano
- Department of Life Sciences, University of Siena, Siena 53100, Italy
| | - Anna Onnis
- Department of Life Sciences, University of Siena, Siena 53100, Italy
| | - Elisa Pappalardo
- Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
| | - Federico Galvagni
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena 53100, Italy
| | - Oreste Acuto
- Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
| | - Cosima T Baldari
- Department of Life Sciences, University of Siena, Siena 53100, Italy
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Trulioff A, Ermakov A, Malashichev Y. Primary Cilia as a Possible Link between Left-Right Asymmetry and Neurodevelopmental Diseases. Genes (Basel) 2017; 8:genes8020048. [PMID: 28125008 PMCID: PMC5333037 DOI: 10.3390/genes8020048] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 12/21/2016] [Accepted: 01/19/2017] [Indexed: 12/11/2022] Open
Abstract
Cilia have multiple functions in the development of the entire organism, and participate in the development and functioning of the central nervous system. In the last decade, studies have shown that they are implicated in the development of the visceral left-right asymmetry in different vertebrates. At the same time, some neuropsychiatric disorders, such as schizophrenia, autism, bipolar disorder, and dyslexia, are known to be associated with lateralization failure. In this review, we consider possible links in the mechanisms of determination of visceral asymmetry and brain lateralization, through cilia. We review the functions of seven genes associated with both cilia, and with neurodevelopmental diseases, keeping in mind their possible role in the establishment of the left-right brain asymmetry.
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Affiliation(s)
- Andrey Trulioff
- Department of Vertebrate Zoology, Faculty of Biology, Saint Petersburg State University, Universitetskaya nab., 7/9, Saint Petersburg 199034, Russia.
| | - Alexander Ermakov
- Department of Vertebrate Zoology, Faculty of Biology, Saint Petersburg State University, Universitetskaya nab., 7/9, Saint Petersburg 199034, Russia.
- Laboratory of Molecular Neurobiology, Department of Ecological Physiology, Institute of Experimental Medicine, ul. Akad. Pavlov, 12, Saint Petersburg 197376, Russia.
| | - Yegor Malashichev
- Department of Vertebrate Zoology, Faculty of Biology, Saint Petersburg State University, Universitetskaya nab., 7/9, Saint Petersburg 199034, Russia.
- Laboratory of Molecular Neurobiology, Department of Ecological Physiology, Institute of Experimental Medicine, ul. Akad. Pavlov, 12, Saint Petersburg 197376, Russia.
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Cardoso MABS, do Nascimento TJ, Bernardo GP, Bernardo LP, Barbosa MMFL, Neto PJN, de Sousa DF, Júnior AGT, de Lima MAP, Moreira MM, de Sousa Gregório D, do Nascimento Santos LC, Rolim Neto ML. Are There Schizophrenia Genetic Markers and Mutations? A Systematic Review and Meta-Analyses. Health (London) 2017. [DOI: 10.4236/health.2017.95058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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50
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Chen CY, Liu HY, Hsueh YP. TLR3 downregulates expression of schizophrenia gene Disc1 via MYD88 to control neuronal morphology. EMBO Rep 2016; 18:169-183. [PMID: 27979975 PMCID: PMC5210159 DOI: 10.15252/embr.201642586] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 11/08/2016] [Accepted: 11/09/2016] [Indexed: 01/28/2023] Open
Abstract
Viral infection during fetal or neonatal stages increases the risk of developing neuropsychiatric disorders such as schizophrenia and autism spectrum disorders. Although neurons express several key regulators of innate immunity, the role of neuronal innate immunity in psychiatric disorders is still unclear. Using cultured neurons and in vivo mouse brain studies, we show here that Toll‐like receptor 3 (TLR3) acts through myeloid differentiation primary response gene 88 (MYD88) to negatively control Disrupted in schizophrenia 1 (Disc1) expression, resulting in impairment of neuronal development. Cytokines are not involved in TLR3‐mediated inhibition of dendrite outgrowth. Instead, TLR3 signaling suppresses expression of several psychiatric disorder‐related genes, including Disc1. The impaired dendritic arborization caused by TLR3 activation is rescued by MYD88 deficiency or DISC1 overexpression. In addition, TLR3 activation at the neonatal stage increases dendritic spine density, but narrows spine heads at postnatal day 21 (P21), suggesting a long‐lasting effect of TLR3 activation on spinogenesis. Our study reveals a novel mechanism of TLR3 in regulation of dendritic morphology and provides an explanation for how environmental factors influence mental health.
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Affiliation(s)
- Chiung-Ya Chen
- Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
| | - Hsin-Yu Liu
- Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
| | - Yi-Ping Hsueh
- Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
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