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.
Highlights
Mammalian histone deacetylases (HDAC) are lysine deacetylases, which are classified into three main groups based on their homology to yeast proteins.HDAC4‐specific siRNA (HDAC4) belongs to group II subgroup A of the family [1]
It was reported that HDAC4 alone does not show deacetylase activity on histone substrate but regulates histone deacetylation through its interaction with HDAC3 [26]
We www.impactaging.com present evidence that HDAC4 impairs the degradation of mutant huntingtin protein (mHTT) aggregates, interacts directly with autophagy activator MAP1S, reduces MAP1S stability, suppresses the autophagy flux mediated by MAP1S, and impairs the degradation of mHTT aggregates
Summary
Mammalian histone deacetylases (HDAC) are lysine deacetylases, which are classified into three main groups based on their homology to yeast proteins. HDAC4 belongs to group II subgroup A of the family [1]. Huntington’s disease (HD) is a fatal progressive neuro-degenerative disorder caused by an autosomal dominant mutation with expansion of more than 36 trinucleotide CAG repeats HDAC4 associates with the mutant HTT (mHTT) and colocalizes with it in cytoplasmic inclusions [3]. In mouse models of Huntington’s disease, HDAC4 reduction delays cytoplasmic formation of mHTT aggregates and rescues neuronal and cortico-striatal synaptic function, but does not repair the global transcriptional dysfunction [3]. The mechanism by which HDAC4 reduction delays cytoplasmic formation of mHTT aggregates is unknown
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
