Regulation of autophagy by neuropathological protein TDP-43

Jayarama Krishnan Bose, Chi Chen Huang, C. K James Shen

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

TDP-43 is a DNA/RNA-binding protein with multicellular functions. As a pathosignature protein of a range of neurodegenerative diseases, TDP-43 is also the major component of the polyubiquitinated inclusions in the pathological cellular samples of these diseases. In normal cells, TDP-43 is processed and degraded by both autophagy and the ubiquitin-proteasome systems. We have found, by microarray hybridization and RT-PCR analyses, that the level of the mRNA encoding the major autophagy component Atg7 is decreased upon depletion of TDP-43 by RNAi knockdown. This decrease of the Atg7 mRNA level could be rescued by overexpression of an siRNA-resistant form of TDP-43, and it appears to be the result of destabilization of the Atg7 mRNA, to which TDP-43 could bind through its RNA recognition motif 1 domain. Furthermore, depletion of TDP-43 with the consequent loss of the Atg7 mRNA/ATG7 protein causes impairment of the autophagy and facilitates the accumulation of polyubiquitinated proteins as well as the autophagy/ubiquitin-proteasome system substrate p62 in the cells. These data demonstrate the function of TDP-43 as a maintenance factor of the autophagy system, and they suggest the existence of a feedback regulatory loop between TDP-43 and autophagy. A scenario in which loss of function of TDP-43 contributes to the development of TDP-43 proteinopathies is presented.

Original languageEnglish
Pages (from-to)44441-44448
Number of pages8
JournalJournal of Biological Chemistry
Volume286
Issue number52
DOIs
Publication statusPublished - Dec 30 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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