Optogenetic TDP-43 nucleation induces persistent insoluble species and progressive motor dysfunction in vivo
| Autor: | Tyler R. Fortuna, Noah J. Pyles, Udai Bhan Pandey, Christopher J. Donnelly, Jacob R. Mann, Nandini Ramesh, Charlton Otte, Amanda M. Gleixner |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cytoplasmic inclusion TDP-43 optoTDP43 RNA-binding protein Optogenetics Article lcsh:RC321-571 03 medical and health sciences 0302 clinical medicine mental disorders medicine Animals ALS/FTD LATE Amyotrophic lateral sclerosis Neurodegeneration lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Cell Nucleus Inclusion Bodies Neurons Chemistry Neurotoxicity RNA nutritional and metabolic diseases Neurodegenerative Diseases medicine.disease Cell biology nervous system diseases DNA-Binding Proteins 030104 developmental biology Neurology Frontotemporal Dementia TDP-43 Proteinopathies Mutation Drosophila RNA binding proteins 030217 neurology & neurosurgery Frontotemporal dementia |
| Zdroj: | Neurobiology of Disease, Vol 146, Iss, Pp 105078-(2020) Neurobiol Dis |
| Popis: | 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, most notably, Amyotrophic Lateral Sclerosis (ALS), a fatal and progressive neuromuscular disorder. 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 aggregation in Drosophila that recapitulates key biochemical features seen in patient pathology, most notably light-inducible persistent insoluble species and progressive motor dysfunction. These data describe a photokinetic in vivo model that could be as a future platform to identify novel genetic and pharmacological modifiers of diseases associated with TDP-43 neuropathology. |
| Databáze: | OpenAIRE |
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