Subcellular localization and ER-mediated cytotoxic function of 1A and 1ACT in spinocerebellar ataxia type 6

Spinocerebellar ataxia type 6 (SCA6) is a polyglutamine (polyQ) disease, which is caused by the elongation of CAG repeats encoding polyQ in the CACNA1A gene. The CACNA1A gene encodes two proteins, namely, alpha 1A (a subunit of the plasma membrane calcium channel), which is translated in its entire length, and alpha 1ACT, which is translated from the second cistron, and both proteins have a polyQ tract. The alpha 1A-polyQ and alpha 1ACT-polyQ proteins with an elongated polyQ stretch have been reported to form aggregates in cells and induce neuronal cell death, but the subcellular localization of these proteins and their cytotoxic properties remain unclear. In this study, we first analyzed SCA6 model mice and found that alpha 1A-polyQlong localized mainly to the Golgi apparatus, whereas a portion of alpha 1ACTpolyQlong localized to the nucleus. Analysis using Neuro2a cells also showed similar subcellular localizations of these proteins, and a proportion of both proteins localized to the endoplasmic reticulum (ER). Cytotoxic studies demonstrated that both proteins induce both the ER stress response and apoptosis, indicating that they are able to induce ER stress-induced apoptosis.