Optogenetic TDP-43 nucleation induces persistent insoluble species and progressive motor dysfunction in vivo

NEUROBIOLOGY OF DISEASE

卷:146

Article

Otte, Charlton G.^1,3,6  Fortuna, Tyler R.⁷  Mann, Jacob R.^2,3,4,5,6  Gleixner, Amanda M.^3,4,5,6  Ramesh, Nandini⁷  Pyles, Noah J.^1,3,6  Pandey, Udai B.^2,5,7  Donnelly, Christopher J.^1,2,3,4,5,6 

[1] Univ Pittsburgh, Sch Med, Phys Scientist Training Program, Pittsburgh, PA 15260 USA

[2] Univ Pittsburgh, Ctr Neurosci, Pittsburgh, PA 15260 USA

[3] Univ Pittsburgh, Sch Med, Dept Neurobiol, Pittsburgh, PA 15260 USA

[4] Univ Pittsburgh, Pittsburgh Inst Neurodegenerat Dis, Pittsburgh, PA 15260 USA

[5] Univ Pittsburgh, Ctr Prot Conformat Dis, Pittsburgh, PA 15260 USA

[6] Univ Pittsburgh, Brain Inst, LiveLikeLou Ctr ALS Res, Pittsburgh, PA 15260 USA

[7] Univ Pittsburgh, Med Ctr, Childrens Hosp Pittsburgh, Dept Pediat, Pittsburgh, PA 15260 USA

关键词: TDP-43;    ALS/FTD;    LATE;    RNA binding proteins;    optoTDP43;    Neurodegeneration;   

DOI  :  10.1016/j.nbd.2020.105078

来源: Elsevier

【 摘 要 】

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.