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The Role of HDAC6 in TDP-43-Induced Neurotoxicity and UPS Impairment

Title
The Role of HDAC6 in TDP-43-Induced Neurotoxicity and UPS Impairment
Authors
Lee, ShinryeKwon, YounghwiKim, SeyeonJo, MyungjinJeon, Yu-MiCheon, MookyungLee, SeongsooKim, Sang RyongKim, KiyoungKim, Hyung-Jun
DGIST Authors
Lee, Shinrye; Kwon, Younghwi; Kim, Seyeon; Jo, Myungjin; Jeon, Yu-Mi; Cheon, Mookyung; Lee, Seongsoo; Kim, Sang Ryong; Kim, Kiyoung; Kim, Hyung-Jun
Issue Date
2020-11
Citation
Frontiers in Cell and Developmental Biology, 8, 581942
Type
Article
Article Type
Article
Author Keywords
tar DNA-binding protein 43histone deacetylase 6ubiquitin-proteasome systemamyotrophic lateral sclerosisautophagy-lysosome pathway
Keywords
UBIQUITIN-PROTEASOME SYSTEMOXIDATIVE STRESSDROSOPHILA MODELGENE-EXPRESSIONMOUSE MODELTDP-43PROTEINAUTOPHAGYPATHOGENESISAGGREGATION
ISSN
2296-634X
Abstract
Transactive response DNA-binding protein 43 (TDP-43)-induced neurotoxicity is currently well recognized as a contributor to the pathology of amyotrophic lateral sclerosis (ALS), and the deposition of TDP-43 has been linked to other neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). Recent studies also suggest that TDP-43-induced neurotoxicity is associated with ubiquitin-proteasome system (UPS) impairment. Histone deacetylase 6 (HDAC6) is a well-known cytosolic deacetylase enzyme that suppresses the toxicity of UPS impairment. However, the role of HDAC6 in TDP-43-induced neurodegeneration is largely unknown. In this study, we found that HDAC6 overexpression decreased the levels of insoluble and cytosolic TDP-43 protein in TDP-43-overexpressing N2a cells. In addition, TDP-43 overexpression upregulated HDAC6 protein and mRNA levels, and knockdown of Hdac6 elevated the total protein level of TDP-43. We further found that HDAC6 modulates TDP-43-induced UPS impairment via the autophagy-lysosome pathway (ALP). We also showed that TDP-43 promoted a short lifespan in flies and that the accumulation of ubiquitin aggregates and climbing defects were significantly rescued by overexpression of HDAC6 in flies. Taken together, these findings suggest that HDAC6 overexpression can mitigate neuronal toxicity caused by TDP-43-induced UPS impairment, which may represent a novel therapeutic approach for ALS.
URI
http://hdl.handle.net/20.500.11750/12829
DOI
10.3389/fcell.2020.581942
Publisher
Frontiers Media S.A.
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