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Divalproex sodium regulates ataxin-3 translocation likely by an importin α1-dependent pathway

Wang, Zijiana,b,c; He, Fengqina; Abeditashi, Mahkamehb,c; Schmidt, Thorstenb,c

doi: 10.1097/WNR.0000000000001246
Degeneration and Repair

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.

aGenetic Engineering Laboratory, College of Biological and Environmental Engineering, Xi’an University, Xi’an, China

bInstitute of Medical Genetics and Applied Genomics, University of Tuebingen

cCenter for Rare Diseases (ZSE), University Hospital Tuebingen, Tuebingen, Germany

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Received 16 October 2018 Accepted 19 March 2019

Correspondence to Zijian Wang, PhD, Genetic Engineering Laboratory, College of Biological and Environmental Engineering, Xi’an University, Keji 6th Road No. 1, 710065 Xi’an, China, Tel: +86 298 824 1902; fax: +86 298 825 8510; e-mail:

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