Molecular Pathogenesis of Spinocerebellar Ataxia Type 6

Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California 92093, USA.
Neurotherapeutics (Impact Factor: 5.05). 04/2007; 4(2):285-94. DOI: 10.1016/j.nurt.2007.01.003
Source: PubMed


Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disorder caused by abnormal expansions of a trinucleotide CAG repeat in exon 47 of the CACNA1A gene, which encodes the alpha1A subunit of the P/Q-type voltage-gated calcium channel. The CAG repeat expansion is translated into an elongated polyglutamine tract in the carboxyl terminus of the alpha1A subunit. The alpha1A subunit is the main pore-forming subunit of the P/Q-type calcium channel. Patients with SCA6 suffer from a severe form of progressive ataxia and cerebellar dysfunction. Design of treatments for this disorder will depend on better definition of the mechanism of disease. As a disease arising from a mutation in an ion channel gene, SCA6 may behave as an ion channelopathy, and may respond to attempts to modulate or correct ion channel function. Alternatively, as a disease in which the mutant protein contains an expanded polyglutamine tract, SCA6 may respond to the targets of drug therapies developed for Huntington's disease and other polyglutamine disorders. In this review we will compare SCA6 to other polyglutamine diseases and channelopathies, and we will highlight recent advances in our understanding of alpha1A subunits and SCA6 pathology. We also propose a mechanism for how two seemingly divergent hypotheses can be combined into a cohesive model for disease progression.

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    • "Two important features of SCA6, however, make it unique among the polyQ diseases. First, SCA6 is caused by a relatively small polyQ expansion in Ca V 2.1, only 20–33 glutamines in length (Kordasiewicz and Gomez, 2007; Zhuchenko et al., 1997). In contrast, expansions of at least 35–38 glutamines are needed to cause disease in the other polyQ disorders. "
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    ABSTRACT: Spinocerebellar ataxia type 6 (SCA6) is an inherited neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the Ca(V)2.1 voltage-gated calcium channel subunit (CACNA1A). There is currently no treatment for this debilitating disorder and thus a pressing need to develop preventative therapies. RNA interference (RNAi) has proven effective at halting disease progression in several models of spinocerebellar ataxia (SCA), including SCA types 1 and 3. However, in SCA6 and other dominantly inherited neurodegenerative disorders, RNAi-based strategies that selectively suppress expression of mutant alleles may be required. Using a Ca(V)2.1 mini-gene reporter system, we found that pathogenic CAG expansions in Ca(V)2.1 enhance splicing activity at the 3'end of the transcript, leading to a CAG repeat length-dependent increase in the levels of a polyQ-encoding Ca(V)2.1 mRNA splice isoform and the resultant disease protein. Taking advantage of this molecular phenomenon, we developed a novel splice isoform-specific (SIS)-RNAi strategy that selectively targets the polyQ-encoding Ca(V)2.1 splice variant. Selective suppression of transiently expressed and endogenous polyQ-encoding Ca(V)2.1 splice variants was achieved in a variety of cell-based models including a human neuronal cell line, using a new artificial miRNA-like delivery system. Moreover, the efficacy of gene silencing correlated with effective intracellular recognition and processing of SIS-RNAi miRNA mimics. These results lend support to the preclinical development of SIS-RNAi as a potential therapy for SCA6 and other dominantly inherited diseases.
    Neurobiology of Disease 04/2011; 43(3):533-42. DOI:10.1016/j.nbd.2011.04.016 · 5.08 Impact Factor
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    • "Various inherited and targeted mutations of Cacna1a and auxiliary subunit genes have been identified in human and mice that cause ataxia, as first described in the tottering mutant and its alleles (Fletcher et al., 1996; Burgess and Noebels, 1999; Mori et al., 2000; Zwingman et al., 2001). Human ataxic phenotypes with cerebellar atrophy include SCA6 and EA2 (Kordasiewicz and Gomez, 2007; Strupp et al., 2007). Mouse models show varying degrees of cerebellar pathology, from minimal dendritic atrophy and PC loss in tottering, to more severe dystrophy in other alleles (Fletcher et al., 1996; Burgess and Noebels, 1999; Mori et al., 2000; Zwingman et al., 2001; Kodama et al., 2006; Sawada et al., 2009; Pietrobon, 2010). "
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    ABSTRACT: Inherited loss of P/Q-type calcium channel function causes human absence epilepsy, episodic dyskinesia, and ataxia, but the molecular "birthdate" of the neurological syndrome and its dependence on prenatal pathophysiology is unknown. Since these channels mediate transmitter release at synapses throughout the brain and are expressed early in embryonic development, delineating the critical circuitry and onset underlying each of the emergent phenotypes requires targeted control of gene expression. To visualize P/Q-type Ca(2+) channels and dissect their role in neuronal networks at distinct developmental stages, we created a novel conditional Cacna1a knock-in mouse by inserting the floxed green fluorescent protein derivative Citrine into the first exon of Cacna1a and then crossed it with a postnatally expressing PCP2-Cre line for delayed Purkinje cell (PC) gene deletion within the cerebellum and sparsely in forebrain (purky). PCs in purky mice lacked P/Q-type calcium channel protein and currents within the first month after birth, displayed altered spontaneous firing, and showed impaired neurotransmission. Unexpectedly, adult purky mice exhibited the full spectrum of neurological deficits seen in mice with genomic Cacna1a ablation. Our results show that the ataxia, dyskinesia, and absence epilepsy caused by inherited disorders of the P/Q-type channel arise from signaling defects beginning in late infancy, revealing an early window of opportunity for therapeutic intervention.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 03/2011; 31(11):4311-26. DOI:10.1523/JNEUROSCI.5342-10.2011 · 6.34 Impact Factor
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    • "As the mutation of SCA6 is in CACNA1A encoding Cav2.1, a pore-forming subunit of P/Q-type voltage-dependent calcium channel essential for neurons [4, 30, 55], it is possible that such small polyQ expansion leads to neurodegeneration by functional alterations of Cav2.1 [5, 14, 21, 28, 35, 36, 50]. However, two recent studies on different SCA6 knock-in mice neither found that expanded polyQ affects the electrophysiological properties of Cav2.1 [37, 57], suggesting that the pathogenic mechanism of polyQ expansion in SCA6 is not merely due to functional changes of Cav2.1. "
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    ABSTRACT: 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 alpha(1A) voltage-dependent calcium channel (Ca(v)2.1). Although a 75-85-kDa Ca(v)2.1 C-terminal fragment (CTF) is toxic in cultured cells, its existence in human brains and its role in SCA6 pathogenesis remains unknown. Here, we investigated whether the small polyQ expansion alters the expression pattern and intracellular distribution of Ca(v)2.1 in human SCA6 brains. New antibodies against the Ca(v)2.1 C-terminus were used in immunoblotting and immunohistochemistry. 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. 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. Immunohistochemistry revealed abundant aggregates in cell bodies and dendrites of SCA6 Purkinje cells (seven patients) but not in controls (n = 6). 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(v)2.1 with Q28 did. 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.
    Acta Neuropathologica 04/2010; 119(4):447-64. DOI:10.1007/s00401-009-0630-0 · 10.76 Impact Factor
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