Second Cistron in CACNA1A Gene Encodes a Transcription Factor Mediating Cerebellar Development and SCA6

The CACNA1A gene, encoding the voltage-gated calcium channel subunit alpha 1A, is involved in pre- and postsynaptic Ca2+ signaling, gene expression, and several genetic neurological disorders. We found that CACNA1A coordinates gene expression using a bicistronic mRNA bearing a cryptic internal ribosomal entry site (IRES). The first cistron encodes the well-characterized alpha 1A subunit. The second expresses a transcription factor, alpha 1ACT, which coordinates expression of a program of genes involved in neural and Purkinje cell development. alpha 1ACT also contains the polyglutamine (polyQ) tract that, when expanded, causes spinocerebellar ataxia type 6 (SCA6). When expressed as an independent polypeptide, alpha 1ACT-bearing an expanded polyQ tract-lacks transcription factor function and neurite outgrowth properties, causes cell death in culture, and leads to ataxia and cerebellar atrophy in transgenic mice. Suppression of CACNA1A IRES function in SCA6 may be a potential therapeutic strategy.