Open AccessDivalproex sodium modulates nuclear localization of ataxin‐3 and prevents cellular toxicity caused by expanded ataxin‐3
Author(s) -
Wang ZiJian,
Hanet Aoife,
Weishäupl Daniel,
Martins Inês M.,
Sowa Anna S.,
Riess Olaf,
Schmidt Thorsten
Publication year - 2018
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.12795
Subject(s) - neurodegeneration , spinocerebellar ataxia , polyglutamine tract , trinucleotide repeat expansion , histone deacetylase inhibitor , histone deacetylase , chemistry , neuroscience , histone , biology , ataxia , medicine , huntington's disease , disease , biochemistry , huntingtin , allele , gene
Summary Background & Aims Spinocerebellar ataxia type 3 ( SCA 3), also known as Machado‐Joseph disease ( MJD ), is an autosomal dominantly inherited neurodegenerative disorder and the most common form of SCA worldwide. It is caused by the expansion of a polyglutamine (polyQ) tract in the ataxin‐3 protein. Nuclear localization of the affected protein is a key event in the pathology of SCA 3 via affecting nuclear organization, transcriptional dysfunction, and seeding aggregations, finally causing neurodegeneration and cell death. So far, there is no effective therapy to prevent or slow the progression of SCA 3. Methods In this study, we explored the effect of divalproex sodium as an HDAC i in SCA 3 cell models and explored how divalproex sodium interferes with pathogenetic processes causing SCA 3. Results We found that divalproex sodium rescues the hypoacetylation levels of histone H3 and attenuates cellular cytotoxicity induced by expanded ataxin‐3 partly via preventing nuclear transport of ataxin‐3 (particularly heat shock‐dependent). Conclusion Our study provides novel insights into the mechanisms of action of divalproex sodium as a possible treatment for SCA 3, beyond the known regulation of transcription.