Increased Expression of α1A Ca2+Channel Currents Arising from Expanded Trinucleotide Repeats in Spinocerebellar Ataxia Type 6

The expansion of polyglutamine tracts encoded by CAG trinucleotide repeats is a common mutational mechanism in inherited neurodegenerative diseases. Spinocerebellar ataxia type 6 (SCA6), an autosomal dominant, progressive disease, arises from trinucleotide repeat expansions present in the coding reg...

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Veröffentlicht in:The Journal of neuroscience 2001-12, Vol.21 (23), p.9185-9193
Hauptverfasser: Piedras-Rentería, Erika S., Watase, Kei, Harata, Nobutoshi, Zhuchenko, Olga, Zoghbi, Huda Y., Lee, Cheng Chi, Tsien, Richard W.
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Sprache:eng
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Zusammenfassung:The expansion of polyglutamine tracts encoded by CAG trinucleotide repeats is a common mutational mechanism in inherited neurodegenerative diseases. Spinocerebellar ataxia type 6 (SCA6), an autosomal dominant, progressive disease, arises from trinucleotide repeat expansions present in the coding region of CACNA1A (chromosome 19p13). This gene encodes α 1A , the principal subunit of P/Q-type Ca 2+ channels, which are abundant in the CNS, particularly in cerebellar Purkinje and granule neurons. We assayed ion channel function by introduction of human α 1A cDNAs in human embryonic kidney 293 cells that stably coexpressed β 1 and α 2 δ subunits. Immunocytochemical analysis showed a rise in intracellular and surface expression of α 1A protein when CAG repeat lengths reached or exceeded the pathogenic range for SCA6. This gain at the protein level was not a consequence of changes in RNA stability, as indicated by Northern blot analysis. The electrophysiological behavior of α 1A subunits containing expanded (EXP) numbers of CAG repeats (23, 27, and 72) was compared against that of wild-type subunits (WT) (4 and 11 repeats) using standard whole-cell patch-clamp recording conditions. The EXP α 1A subunits yielded functional ion channels that supported inward Ca 2+ channel currents, with a sharp increase in P/Q Ca 2+ channel current density relative to WT. Our results showed that Ca 2+ channels from SCA6 patients display near-normal biophysical properties but increased current density attributable to elevated protein expression at the cell surface.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.21-23-09185.2001