Polyglutamine length-dependent toxicity from α1ACT in Drosophila models of spinocerebellar ataxia type 6

Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease that results from abnormal expansion of a polyglutamine (polyQ) repeat. SCA6 is caused by CAG triplet repeat expansion in the gene CACNA1A, resulting in a polyQ tract of 19-33 in patients. CACNA1A, a bicistronic gene, encodes the alpha 1A calcium channel subunit and the transcription factor, alpha 1ACT. PolyQ expansion in alpha 1ACT causes degeneration in mice. We recently described the first Drosophila models of SCA6 that express alpha 1ACT with a normal (11Q) or hyper-expanded (70Q) polyQ. Here, we report additional alpha 1ACT transgenic flies, which express full-length alpha 1ACT with a 33Q repeat. We show that alpha 1ACT33Q is toxic in Drosophila, but less so than the 70Q version. When expressed everywhere, alpha 1ACT33Q-expressing adults die earlier than flies expressing the normal allele. alpha 1ACT33Q causes retinal degeneration and leads to aggregated species in an age-dependent manner, but at a slower pace than the 70Q counterpart. According to western blots, alpha 1ACT33Q localizes less readily in the nucleus than alpha 1ACT70Q, providing clues into the importance of polyQ tract length on alpha 1ACT localization and its site of toxicity. We expect that these new lines will be highly valuable for future work on SCA6.