Optogenetic TDP-43 nucleation induces persistent insoluble species and progressive motor dysfunction in vivo
TDP-43 is a predominantly nuclear DNA/RNA binding protein that is often mislocalized into insoluble cytoplasmic inclusions in post-mortem patient tissue in a variety of neurodegenerative disorders including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD). The underlying causes...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-12-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996120303533 |
| _version_ | 1818610565469175808 |
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| author | Charlton G. Otte Tyler R. Fortuna Jacob R. Mann Amanda M. Gleixner Nandini Ramesh Noah J. Pyles Udai B. Pandey Christopher J. Donnelly |
| author_facet | Charlton G. Otte Tyler R. Fortuna Jacob R. Mann Amanda M. Gleixner Nandini Ramesh Noah J. Pyles Udai B. Pandey Christopher J. Donnelly |
| author_sort | Charlton G. Otte |
| collection | DOAJ |
| description | TDP-43 is a predominantly nuclear DNA/RNA binding protein that is often mislocalized into insoluble cytoplasmic inclusions in post-mortem patient tissue in a variety of neurodegenerative disorders including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD). The underlying causes of TDP-43 proteinopathies remain unclear, but recent studies indicate the formation of these protein assemblies is driven by aberrant phase transitions of RNA deficient TDP-43. Technical limitations have prevented our ability to understand how TDP-43 proteinopathy relates to disease pathogenesis. Current animal models of TDP-43 proteinopathy often rely on overexpression of wild-type TDP-43 to non-physiological levels that may initiate neurotoxicity through nuclear gain of function mechanisms, or by the expression of disease-causing mutations found in only a fraction of ALS patients. New technologies allowing for light-responsive control of subcellular protein crowding provide a promising approach to drive intracellular protein aggregation, as we have previously demonstrated in vitro. Here we present a model for the optogenetic induction of TDP-43 proteinopathy in Drosophila that recapitulates key features of patient pathology, including detergent insoluble cytoplamsic inclusions and progressive motor dysfunction. |
| first_indexed | 2024-12-16T15:16:27Z |
| format | Article |
| id | doaj.art-baa924d59c9e4f35af49422a6a7a2c8d |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-16T15:16:27Z |
| publishDate | 2020-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-baa924d59c9e4f35af49422a6a7a2c8d2022-12-21T22:26:47ZengElsevierNeurobiology of Disease1095-953X2020-12-01146105078Optogenetic TDP-43 nucleation induces persistent insoluble species and progressive motor dysfunction in vivoCharlton G. Otte0Tyler R. Fortuna1Jacob R. Mann2Amanda M. Gleixner3Nandini Ramesh4Noah J. Pyles5Udai B. Pandey6Christopher J. Donnelly7Physician Scientist Training Program, University of Pittsburgh School of Medicine, United States of America; Department of Neurobiology, University of Pittsburgh School of Medicine, United States of America; LiveLikeLou Center for ALS Research, University of Pittsburgh Brain Institute, United States of AmericaDepartment of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, United States of AmericaCenter for Neuroscience, University of Pittsburgh, United States of America; Department of Neurobiology, University of Pittsburgh School of Medicine, United States of America; Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, United States of America; Center for Protein Conformational Diseases, University of Pittsburgh, United States of America; LiveLikeLou Center for ALS Research, University of Pittsburgh Brain Institute, United States of AmericaDepartment of Neurobiology, University of Pittsburgh School of Medicine, United States of America; Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, United States of America; Center for Protein Conformational Diseases, University of Pittsburgh, United States of America; LiveLikeLou Center for ALS Research, University of Pittsburgh Brain Institute, United States of AmericaDepartment of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, United States of AmericaPhysician Scientist Training Program, University of Pittsburgh School of Medicine, United States of America; Department of Neurobiology, University of Pittsburgh School of Medicine, United States of America; LiveLikeLou Center for ALS Research, University of Pittsburgh Brain Institute, United States of AmericaCenter for Neuroscience, University of Pittsburgh, United States of America; Center for Protein Conformational Diseases, University of Pittsburgh, United States of America; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, United States of AmericaPhysician Scientist Training Program, University of Pittsburgh School of Medicine, United States of America; Center for Neuroscience, University of Pittsburgh, United States of America; Department of Neurobiology, University of Pittsburgh School of Medicine, United States of America; Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, United States of America; Center for Protein Conformational Diseases, University of Pittsburgh, United States of America; LiveLikeLou Center for ALS Research, University of Pittsburgh Brain Institute, United States of America; Corresponding author at: Department of Neurobiology, University of Pittsburgh School of Medicine, United States of America.TDP-43 is a predominantly nuclear DNA/RNA binding protein that is often mislocalized into insoluble cytoplasmic inclusions in post-mortem patient tissue in a variety of neurodegenerative disorders including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD). The underlying causes of TDP-43 proteinopathies remain unclear, but recent studies indicate the formation of these protein assemblies is driven by aberrant phase transitions of RNA deficient TDP-43. Technical limitations have prevented our ability to understand how TDP-43 proteinopathy relates to disease pathogenesis. Current animal models of TDP-43 proteinopathy often rely on overexpression of wild-type TDP-43 to non-physiological levels that may initiate neurotoxicity through nuclear gain of function mechanisms, or by the expression of disease-causing mutations found in only a fraction of ALS patients. New technologies allowing for light-responsive control of subcellular protein crowding provide a promising approach to drive intracellular protein aggregation, as we have previously demonstrated in vitro. Here we present a model for the optogenetic induction of TDP-43 proteinopathy in Drosophila that recapitulates key features of patient pathology, including detergent insoluble cytoplamsic inclusions and progressive motor dysfunction.http://www.sciencedirect.com/science/article/pii/S0969996120303533TDP-43ALS/FTDLATERNA binding proteinsoptoTDP43Neurodegeneration |
| spellingShingle | Charlton G. Otte Tyler R. Fortuna Jacob R. Mann Amanda M. Gleixner Nandini Ramesh Noah J. Pyles Udai B. Pandey Christopher J. Donnelly Optogenetic TDP-43 nucleation induces persistent insoluble species and progressive motor dysfunction in vivo Neurobiology of Disease TDP-43 ALS/FTD LATE RNA binding proteins optoTDP43 Neurodegeneration |
| title | Optogenetic TDP-43 nucleation induces persistent insoluble species and progressive motor dysfunction in vivo |
| title_full | Optogenetic TDP-43 nucleation induces persistent insoluble species and progressive motor dysfunction in vivo |
| title_fullStr | Optogenetic TDP-43 nucleation induces persistent insoluble species and progressive motor dysfunction in vivo |
| title_full_unstemmed | Optogenetic TDP-43 nucleation induces persistent insoluble species and progressive motor dysfunction in vivo |
| title_short | Optogenetic TDP-43 nucleation induces persistent insoluble species and progressive motor dysfunction in vivo |
| title_sort | optogenetic tdp 43 nucleation induces persistent insoluble species and progressive motor dysfunction in vivo |
| topic | TDP-43 ALS/FTD LATE RNA binding proteins optoTDP43 Neurodegeneration |
| url | http://www.sciencedirect.com/science/article/pii/S0969996120303533 |
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