Research Paper Volume 7, Issue 10 pp 839—853

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

Fei Yue 1, , Wenjiao Li 1, , Jing Zou 1, , Qi Chen 1, , Guibin Xu 1, 2, , Hai Huang 1, 3, , Zhen Xu 4, , Sheng Zhang 4, , Paola Gallinari 5, , Fen Wang 1, , Wallace L. McKeehan 1, , Leyuan Liu 1, 6, ,

  • 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

received: September 6, 2015 ; accepted: September 28, 2015 ; published: October 24, 2015 ;

https://doi.org/10.18632/aging.100818
How to Cite

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.

Abbreviations

AGERA: Agarose Gel Electrophoresis for Resolving Aggregates; BAF: Bafilomycin A1; HBD: HDAC4-binding domain; HBDΔ: MAP1S with HBD deleted; HD: Huntington's disease; HDAC4: histone deacetylase4; K520R: lysine to arginine mutation at amino-acid residue 520; LC3: light chain 3; MAP1S: microtubule-associated protein family 1 small form; mHTT: mutant huntingtin; HTT72Q: Huntingtin gene plus 72 expanded polyglutamine [poly(Q)]; LAMP2: lysosomal-associated membrane protein 2; N2a: Neuroblstoma Neuro-2a.