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

Autor: Otte CG; Physician 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 America., Fortuna TR; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, United States of America., Mann JR; 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., Gleixner AM; 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., Ramesh N; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, United States of America., Pyles NJ; Physician 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 America., Pandey UB; Center 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 America., Donnelly CJ; Physician 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. Electronic address: cjdon25@pitt.edu.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2020 Dec; Vol. 146, pp. 105078. Date of Electronic Publication: 2020 Sep 12.
DOI: 10.1016/j.nbd.2020.105078
Abstrakt: 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.
(Copyright © 2020. Published by Elsevier Inc.)
Databáze: MEDLINE
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