Abstract
ABSTRACTSpinocerebellar 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 α1A calcium channel subunit and the transcription factor, α1ACT. PolyQ expansion in α1ACT causes degeneration in mice. We recently described the first Drosophila models of SCA6 that express α1ACT with a normal (11Q) or hyper-expanded (70Q) polyQ. Here, we report additional α1ACT transgenic flies, which express full-length α1ACT with a 33Q repeat. We show that α1ACT33Q is toxic in Drosophila, but less so than the 70Q version. When expressed everywhere, α1ACT33Q-expressing adults die earlier than flies expressing the normal allele. α1ACT33Q 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, α1ACT33Q localizes less readily in the nucleus than α1ACT70Q, providing clues into the importance of polyQ tract length on α1ACT localization and its site of toxicity. We expect that these new lines will be highly valuable for future work on SCA6.
Highlights
Spinocerebellar ataxia type 6 (SCA6) is an age-dependent neurodegenerative disease caused by anomalous expansion in the CAG triplet repeat in the gene CACNA1A (Orr, 2012; Todi et al, 2007)
The full-length α1ACT cDNA with a 33 CAG repeat was sub-cloned into the pWALIUM10.moe vector (Fig. 1B), which led to single-copy, phiC31-dependent insertion (Groth et al, 2004) into the attp2 site on Drosophila’s third chromosome
We described an additional model of SCA6 in Drosophila that depends on the expression of the full-length α1ACT protein with a human disease range polyQ repeat of 33
Summary
Spinocerebellar ataxia type 6 (SCA6) is an age-dependent neurodegenerative disease caused by anomalous expansion in the CAG triplet repeat in the gene CACNA1A (Orr, 2012; Todi et al, 2007). Symptoms for SCA6 consist predominantly of a ‘pure’ gait ataxia that can be accompanied by tremors, visual symptoms and episodic vertigo. The CAG repeat in CACNA1A encodes a polyglutamine ( polyQ) repeat, classifying SCA6 as one of the members of the polyQ family of neurodegenerative diseases Similar to those disorders, which include Huntington’s disease and several other SCAs, there is no cure for SCA6 (Du et al, 2013; Miyazaki et al, 2016; Williams and Paulson, 2008).
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