Divalproex sodium regulates ataxin-3 translocation likely by an importin α1-dependent pathway
| Autor: | Zi‐Jian Wang, Fengqin He, Mahkameh Abeditashi, Thorsten Schmidt |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
alpha Karyopherins Gene Expression Importin CHO Cells environment and public health 03 medical and health sciences 0302 clinical medicine Cricetulus Animals Humans Ataxin-3 Cell Nucleus Chemistry General Neuroscience Valproic Acid HEK 293 cells Machado-Joseph Disease Transport protein Cell biology Protein Transport 030104 developmental biology HEK293 Cells Acetylation Ataxin embryonic structures Histone deacetylase Nuclear transport 030217 neurology & neurosurgery Nuclear localization sequence Signal Transduction |
| Zdroj: | Neuroreport. 30(11) |
| ISSN: | 1473-558X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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