Bicistronic CACNA1A Gene Expression in Neurons Derived from Spinocerebellar Ataxia Type 6 Patient-Induced Pluripotent Stem Cells.

ABSTRACT: Spinocerebellar ataxia type 6 (SCA6) is an autosomal-dominant neurodegenerative disorder that is caused by a CAG trinucleotide repeat expansion in the CACNA1A gene. As one of the few bicistronic genes discovered in the human genome, CACNA1A encodes not only the ?1A subunit of the P/Q type voltage-gated Ca²⁺ channel Ca_V2.1 but also the ?1ACT protein, a 75?kDa transcription factor sharing the sequence of the cytoplasmic C-terminal tail of the ?1A subunit. Isoforms of both proteins contain the polyglutamine (polyQ) domain that is expanded in SCA6 patients. Although certain SCA6 phenotypes appear to be specific for Purkinje neurons, other pathogenic effects of the SCA6 polyQ mutation can affect a broad spectrum of central nervous system (CNS) neuronal subtypes. We investigated the expression and function of CACNA1A gene products in human neurons derived from induced pluripotent stem cells from two SCA6 patients. Expression levels of CACNA1A encoding ?1A subunit were similar between SCA6 and control neurons, and no differences were found in the subcellular distribution of Ca_V2.1 channel protein. The ?1ACT immunoreactivity was detected in the majority of cell nuclei of SCA6 and control neurons. Although no SCA6 genotype-dependent differences in Ca_V2.1 channel function were observed, they were found in the expression levels of the ?1ACT target gene Granulin (GRN) and in glutamate-induced cell vulnerability.

SUBMITTER: Bavassano C 

PROVIDER: S-EPMC5684673 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature