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

Neurobiology of Disease

Christopher J. Donnelly¹  Noah J. Pyles²  Tyler R. Fortuna²  Jacob R. Mann³  Udai B. Pandey⁴  Nandini Ramesh⁵  Amanda M. Gleixner⁶  Charlton G. Otte⁷ 

[1] Center for Protein Conformational Diseases, University of Pittsburgh, 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 America;Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, United States of America;Center for Neuroscience, University of Pittsburgh, United States of America;Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, United States of America;Physician Scientist Training Program, University of Pittsburgh School of Medicine, United States of America;

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

DOI  :  

来源: DOAJ

【 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.

【 授权许可】

Unknown