9/13/2023 0 Comments Calcium fragment 3![]() ![]() In SCA6, the Ca v2.1 forms microscopic aggregates in Purkinje cells. It has been known that Ca v2.1 is highly expressed in cerebellar neurons and localizes primarily to nerve terminals, dendrites and Purkinje cell soma. However, two recent studies on different SCA6 knock-in mice neither found that expanded polyQ affects the electrophysiological properties of Ca v2.1, suggesting that the pathogenic mechanism of polyQ expansion in SCA6 is not merely due to functional changes of Ca v2.1. Remarkably, CAG repeat/polyQ expansion in SCA6 is smaller than normal-length CAG repeats/polyQs in other polyQ diseases.Īs the mutation of SCA6 is in CACNA1A encoding Ca v2.1, a pore-forming subunit of P/Q-type voltage-dependent calcium channel essential for neurons, it is possible that such small polyQ expansion leads to neurodegeneration by functional alterations of Ca v2.1. The CAG repeat in CACNA1A in normal individuals ranges from 4 to 20 repeats, whereas in SCA6 patients, this repeat is expanded usually ranging from 20 to 28 repeats, although longer expansions up to 33 repeats are rarely found. This is because the CAG repeat, which is transcribed into two different CACNA1A mRNA isoforms by an alternative splicing at the intron46/exon47 splice junction, is placed within a 3′-extended coding sequence of the major mRNA isoform, resulting in the CAG repeat being translated into a polyQ tract. SCA6 is considered one of at least nine known neurodegenerative disorders called polyglutamine (polyQ) diseases, which includes Huntington’s disease (HD), spinal and bulbar muscular atrophy (SBMA), SCA1, SCA2, Machado-Joseph disease/SCA3 (MJD), SCA7, SCA17, and dentatorubral-pallidoluysian atrophy (DRPLA). SCA6 is found worldwide, with a relatively higher prevalence in Japanese. Thus, SCA6 is a prototype of cerebellar cortical degeneration, though degenerations outside the cerebello-olivary system may accompany. In some cases, the inferior olivary complex may be affected. Neuropathologically, degeneration is predominant in cerebellar Purkinje cells showing cerebellar cortical degeneration. Besides progressive cerebellar ataxia, vertigo, oscillopsia, and episodic nature of cerebellar symptoms are characteristic features of SCA6 differentiating from other ataxias. Clinically, SCA6 patients show progressive cerebellar ataxia with an average age of onset at 45.5 years. SCA6 is allelic with three other dominantly inherited neurological diseases caused by different mutations in CACNA1A: episodic ataxia type 2, familial hemiplegic migraine, and progressive cerebellar ataxia. Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant neurodegenerative disease caused by an expansion of a CAG repeat in exon 47 (the final exon) of the α 1A voltage-dependent calcium channel (Ca v2.1) (gene symbol: CACNA1A). We conclude that SCA6 pathogenesis may be associated with the CTF, normally found in the cytoplasm, being aggregated in the cytoplasm and additionally distributed in the nucleus. Recombinant CTF with a small polyQ expansion (rCTF-Q28) aggregated in cultured PC12 cells, but neither rCTF-Q13 (normal-length polyQ) nor full-length Ca v2.1 with Q28 did. Immunohistochemistry revealed abundant aggregates in cell bodies and dendrites of SCA6 Purkinje cells (seven patients) but not in controls ( n = 6). In contrast, however, the CTF was not detected either in the nuclear fraction or in the SDS-insoluble cytosolic fraction of SCA6 extracerebellar tissues, indicating that the CTF being insoluble in the cytoplasm or mislocalized to the nucleus only in the SCA6 cerebellum. In the cerebella of six control individuals, the CTF was detected in sucrose- and SDS-soluble cytosolic fractions in the cerebella of two SCA6 patients, it was additionally detected in SDS-insoluble cytosolic and sucrose-soluble nuclear fractions. New antibodies against the Ca v2.1 C-terminus were used in immunoblotting and immunohistochemistry. Here, we investigated whether the small polyQ expansion alters the expression pattern and intracellular distribution of Ca v2.1 in human SCA6 brains. Although a 75–85-kDa Ca v2.1 C-terminal fragment (CTF) is toxic in cultured cells, its existence in human brains and its role in SCA6 pathogenesis remains unknown. Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant neurodegenerative disease caused by a small polyglutamine (polyQ) expansion (control: 4–20Q SCA6: 20–33Q) in the carboxyl(C)-terminal cytoplasmic domain of the α 1A voltage-dependent calcium channel (Ca v2.1). ![]()
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