Bicistronic CACNA1A Gene Expression in Neurons Derived from Spinocerebellar Ataxia Type 6 Patient-Induced Pluripotent Stem Cells
| Autor: | Georg Dechant, Gerald J. Obermair, Roxana Nat, Carlo Bavassano, Ruslan Stanika, Sylvia Boesch, Andreas Eigentler |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities CACNA1A gene Induced Pluripotent Stem Cells CaV2.1 iPSC-derived neurons Cav2.1 polyQ 03 medical and health sciences 0302 clinical medicine Original Research Reports SCA6 mental disorders medicine Humans Spinocerebellar Ataxias Spinocerebellar ataxia type 6 Induced pluripotent stem cell Neurons α1ACT biology Cell Biology Hematology medicine.disease Molecular biology nervous system diseases 030104 developmental biology Gene Expression Regulation biology.protein Calcium Channels Trinucleotide Repeat Expansion Trinucleotide repeat expansion glutamate-induced stress 030217 neurology & neurosurgery Transcription Factors Developmental Biology |
| Zdroj: | Stem Cells and Development |
| ISSN: | 1557-8534 1547-3287 |
| DOI: | 10.1089/scd.2017.0085 |
| Popis: | 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 α1A subunit of the P/Q type voltage-gated Ca2+ channel CaV2.1 but also the α1ACT protein, a 75 kDa transcription factor sharing the sequence of the cytoplasmic C-terminal tail of the α1A 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 α1A subunit were similar between SCA6 and control neurons, and no differences were found in the subcellular distribution of CaV2.1 channel protein. The α1ACT immunoreactivity was detected in the majority of cell nuclei of SCA6 and control neurons. Although no SCA6 genotype-dependent differences in CaV2.1 channel function were observed, they were found in the expression levels of the α1ACT target gene Granulin (GRN) and in glutamate-induced cell vulnerability. |
| Databáze: | OpenAIRE |
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