Degradation of TDP-43 and its pathogenic form by autophagy and the ubiquitin-proteasome system.
TAR DNA-binding protein-43 (TDP-43) is a nuclear protein functioning in the regulation of transcription and mRNA splicing. TDP-43 is accumulated in ubiquitinated inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS) diseased brains. However, the pathways involved in the clearance of TDP-43 and its pathogenic form (TDP-25), a truncated form of TDP-43, are still not elucidated. In this study, we demonstrated that the protein levels of TDP-43 and TDP-25 were increased in cells treated with a proteasome inhibitor, MG132, or an autophagy inhibitor, 3-MA, whereas, they were decreased in cells treated with an enhancer of autophagy, trehalose. Furthermore, more protein level changes of TDP-25 than TDP-43 were observed in cells treated with above inhibitors or enhancer. Thus, our data suggest that TDP-43 and TDP-25 are degraded by both proteasome and autophagy with TDP-25 being more regulated.
Wang
Xiaoju
X
Hefei National Laboratory for Physical Sciences at Microscale and Department of Neurobiology, School of Life Sciences, University of Science & Technology of China, 443 Huangshan Road, Hefei, Anhui 230027, People's Republic of China.
Fan
Huadong
H
Ying
Zheng
Z
Li
Bin
B
Wang
Hongfeng
H
Wang
Guanghui
G
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D001343:Autophagy; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D010436:Pepstatins / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D061988:Proteasome Inhibitors; D014199:Trehalose / Q000494:pharmacology; D025801:Ubiquitin / Q000502:physiology*
D004268:DNA-Binding Proteins; D007976:Leupeptins; D010436:Pepstatins; D010446:Peptide Fragments; D061988:Proteasome Inhibitors; C574535:TDP-25 protein, human; D025801:Ubiquitin; C025946:3-methyladenine; D014199:Trehalose; D046988:Proteasome Endopeptidase Complex; D000225:Adenine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; C031375:pepstatin