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Aging (Albany NY). 2015 Oct;7(10):839-53.

Blocking the association of HDAC4 with MAP1S accelerates autophagy clearance of mutant Huntingtin.

Author information

1
Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.
2
Department of Urology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China.
3
Department of Urology, The Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
4
The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health, Science Center at Houston, Houston, TX 77030, USA.
5
Exiris Srl, Rome, Italy.
6
Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, TX 77843, USA.

Abstract

Autophagy controls and executes the turnover of abnormally aggregated proteins. MAP1S interacts with the autophagy marker LC3 and positively regulates autophagy flux. HDAC4 associates with the aggregation-prone mutant huntingtin protein (mHTT) that causes Huntington's disease, and colocalizes with it in cytosolic inclusions. It was suggested HDAC4 interacts with MAP1S in a yeast two-hybrid screening. Here, we found that MAP1S interacts with HDAC4 via a HDAC4-binding domain (HBD). HDAC4 destabilizes MAP1S, suppresses autophagy flux and promotes the accumulation of mHTT aggregates. This occurs by an increase in the deacetylation of the acetylated MAP1S. Either suppression of HDAC4 with siRNA or overexpression of the MAP1S HBD leads to stabilization of MAP1S, activation of autophagy flux and clearance of mHTT aggregates. Therefore, specific interruption of the HDAC4-MAP1S interaction with short peptides or small molecules to enhance autophagy flux may relieve the toxicity of mHTT associated with Huntington's disease and improve symptoms of HD patients.

KEYWORDS:

AGERA; C19ORF5; CRISP/Cas9 system; HDAC4; LC3; MAP1S; N2a; acetylation; aggregate; apicidin; autophagy; deacetylase; huntingtin; huntington's disease; stability

PMID:
26540094
PMCID:
PMC4637209
DOI:
10.18632/aging.100818
[Indexed for MEDLINE]
Free PMC Article

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