SQSTM1-mediated clearance of cytoplasmic mutant TARDBP/TDP-43 in the monkey brain

Autophagy. 2022 Aug;18(8):1955-1968. doi: 10.1080/15548627.2021.2013653. Epub 2021 Dec 22.

Abstract

The cytoplasmic accumulation and aggregates of TARDBP/TDP-43 (TAR DNA binding protein) are a pathological hallmark in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We previously reported that the primate specific cleavage of TARDBP accounts for its cytoplasmic mislocalization in the primate brains, prompting us to further investigate how the cytoplasmic TARDBP mediates neuropathology. Here we reported that cytoplasmic mutant TARDBP reduced SQSTM1 expression selectively in the monkey brain, when compared with the mouse brain, by inducing SQSTM1 mRNA instability via its binding to the unique 3'UTR sequence (GU/UG)n of the primate SQSTM1 transcript. Overexpression of SQSTM1 could diminish the cytoplasmic C-terminal TARDBP accumulation in the monkey brain by augmenting macroautophagy/autophagy activity. Our findings provide additional clues for the pathogenesis of cytoplasmic TARDBP and a potential therapy for mutant TARDBP-mediated neuropathology.

Keywords: Aggregate; RNA instability; SQSTM1; TARDBP; non-human primate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis* / metabolism
  • Animals
  • Autophagy* / genetics
  • Brain / metabolism
  • DNA-Binding Proteins* / genetics
  • DNA-Binding Proteins* / metabolism
  • Disease Models, Animal
  • Haplorhini / metabolism
  • Sequestosome-1 Protein* / genetics
  • Sequestosome-1 Protein* / metabolism

Substances

  • DNA-Binding Proteins
  • Sequestosome-1 Protein

Associated data

  • figshare/10.6084/m9.figshare.16836643

Grants and funding

This work was supported by Key Field Research and Development Program of Guangdong province (2018B030337001), Guangzhou Key Research Program on Brain Science (202007030008), The National Key Research and Development Program of China Stem Cell and Translational Research [2017YFA0105102, 2017YFA0105201], The National Natural Science Foundation of China [81830032, 31872779, 82071421, 32070534], Department of Science and Technology of Guangdong Province [2021ZT09Y007; 2020B121201006].