Bicistronic CACNA1A Gene Expression in Neurons Derived from Spinocerebellar Ataxia Type 6 Patient-Induced Pluripotent Stem Cells.
Bicistronic CACNA1A Gene Expression in Neurons Derived from Spinocerebellar Ataxia Type 6 Patient-Induced Pluripotent Stem Cells.
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DOI：
10.1089/scd.2017.0085
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发表时间：
2017-11-15
影响因子：
4
通讯作者：
Nat R
中科院分区：
文献类型：
--
作者：
Bavassano C;Eigentler A;Stanika R;Obermair GJ;Boesch S;Dechant G;Nat R
脊髓小脑性共济失调6型（SCA 6）是一种常染色体显性遗传的神经退行性疾病，由CACNA 1A基因中的CAG三核苷酸重复扩增引起。CACNA 1A是目前在人类基因组中发现的少数双顺反子基因之一，它不仅编码P/Q型电压门控钙通道CaV2.1的α1A亚基，还编码与α1A亚基胞质C末端序列相同的75 kDa转录因子α1ACT蛋白。两种蛋白质的同种型都含有在SCA 6患者中扩增的多聚谷氨酰胺（polyQ）结构域。尽管某些SCA 6表型似乎对浦肯野神经元具有特异性，但SCA 6 polyQ突变的其他致病作用可影响广泛的中枢神经系统（CNS）神经元亚型。我们研究了CACNA 1A基因产物在来自两名SCA 6患者的诱导多能干细胞的人类神经元中的表达和功能。SCA 6和对照神经元中编码α1A亚基的CACNA 1A的表达水平相似，CaV2.1通道蛋白的亚细胞分布无差异。在SCA 6和对照神经元的大部分细胞核中检测到α1ACT免疫反应性。虽然没有观察到CaV2.1通道功能的SCA 6基因型依赖性差异，但在α1ACT靶基因颗粒蛋白（GRN）的表达水平和谷氨酸诱导的细胞脆弱性中发现了这些差异。
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.
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影响因子：
4.3
作者：
Lewerenz J;Maher P
通讯作者：
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影响因子：
5.3
作者：
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通讯作者：
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DOI：
10.1073/pnas.0804350105
发表时间：
2008-08-19
影响因子：
11.1
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通讯作者：
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影响因子：
3.3
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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