Divalproex sodium regulates ataxin-3 translocation likely by an importin α1-dependent pathway.
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| Abstract |
Nuclear localization of ataxin-3 plays a fundamental role in seeding aggregation and the pathology of spinocerebellar ataxia type 3 (SCA3). However, very few compounds that are able to modulate the nuclear transport of ataxin-3 have been identified. In our previous study, we found that divalproex sodium (DVS) reduced heat shock-induced nuclear localization of ataxin-3. However, the mechanism of DVS in the translocation of ataxin-3 still remains unknown. There is accumulating evidence that importins are regulated by acetylation, and histone deacetylase inhibitors can interrupt this process. With this in mind, we used cells coexpressing ataxin-3 and importin α1 (encoded by KNPA2) to probe whether ataxin-3 is the shuttling cargo of importins and whether DVS plays a role in the nuclear transport of ataxin-3 through the transport protein pathway. Here, we reported that importin α1 enhanced nuclear amount of ataxin-3 and increased the aggregate formation and that DVS restored it to the normal level. Importantly, ataxin-3 is shown to directly bind to importin α1. Moreover, DVS modulated the function of importin α1 likely by altering its localization. We believe that this study provides a proof of principle for addressing the mechanism of DVS and furthers our understanding of the role of importins in the nuclear accumulation of ataxin-3 in SCA3.
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| Authors | Zijian Wang, Fengqin He, Mahkameh Abeditashi, Thorsten Schmidt |
| Journal | Neuroreport (Neuroreport) Vol. 30 Issue 11 Pg. 760-764 (08 07 2019) ISSN: 1473-558X [Electronic] England |
| PMID | 31107713 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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