Disulfiram facilitates ataxin-3 nuclear translocation and potentiates the cytotoxicity in a cell model of SCA3.

Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of a glutamine-encoding CAG repeat in the ATXN3 gene encoding the protein ataxin-3. The nuclear presence of polyglutamine-expanded ataxin-3 is of critical importance for the pathogenesis of SCA3. Disulfiram, an FDA-approved drug for alcoholism, has also garnered attention in cancer treatment. However, it has shown toxicity in the nervous system. Bearing this in mind, we treated cells expressing ataxin-3 with disulfiram to measure several pathogenic cascades of SCA3, including aggregate formation, soluble ataxin-3 expression and nuclear localization of ataxin-3 and the cytotoxicity, which assess the direct effect of disulfiram on SCA3 cell models. To our knowledge, this is direct evidence that disulfiram elevated the nuclear localization of polyglutamine-expanded ataxin-3 and enhanced the cytotoxicity in a cell model of SCA3. Furthermore, disulfiram did not affect the aggregate formation of polyglutamine-expanded ataxin-3 at least at a single dose. Our findings repurpose disulfiram as a modulator of ataxin-3 nuclear transport that aggravates the pathology of SCA3, which is a new target for disulfiram. This study also represents an important example of determining novel side effects in pre-existing drugs. This study suggests that caution may be warranted when this compound is used to treat alcohol abuse or cancer in patients carrying a SCA3-causing mutation.