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 |
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Format: | Artikel |
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. |
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ISSN: | 0270-6474 1529-2401 |
DOI: | 10.1523/JNEUROSCI.21-23-09185.2001 |