| RRC ID |
83105
|
| Author |
Otte CG, Fortuna TR, Mann JR, Gleixner AM, Ramesh N, Pyles NJ, Pandey UB, Donnelly CJ.
|
| Title |
Optogenetic TDP-43 nucleation induces persistent insoluble species and progressive motor dysfunction in vivo.
|
| Journal |
Neurobiol Dis
|
| Abstract |
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.
|
| Volume |
146
|
| Pages |
105078
|
| Published |
2020-12-1
|
| DOI |
10.1016/j.nbd.2020.105078
|
| PII |
S0969-9961(20)30353-3
|
| PMID |
32927062
|
| PMC |
PMC9040199
|
| MeSH |
Animals
Cell Nucleus / metabolism
DNA-Binding Proteins / metabolism
Drosophila
Frontotemporal Dementia / genetics*
Frontotemporal Dementia / pathology
Inclusion Bodies / metabolism*
Mutation / genetics*
Neurodegenerative Diseases / genetics
Neurodegenerative Diseases / metabolism
Neurons / metabolism
Optogenetics / methods
TDP-43 Proteinopathies / genetics*
|
| IF |
5.332
|
| Resource |
| Zebrafish |
SAIGFF213A, mnr2b-hs:EGFP-TDP-43z, UAS:opTDP-43z |
