title: Regulation of autophagy by neuropathological protein TDP-43.
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.
authors: Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
authors: Jayarama Krishnan
authors: JK
authors: Bose
authors: Chi-Chen
authors: CC
authors: Huang
authors: C-K James
authors: CK
authors: Shen
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D057177:TDP-43 Proteinopathies / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology
chemical_list: C502661:Atg7 protein, mouse; D004268:DNA-Binding Proteins; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D000071193:Autophagy-Related Protein 7