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The Journal of Neuroscience, 1999, 0:RC14:1-5

RAPID COMMUNICATION
Direct Alteration of the P/Q-Type Ca²⁺ Channel Property by Polyglutamine Expansion in Spinocerebellar Ataxia 6

Zenjiro Matsuyama^{1, 2}, Minoru Wakamori¹, Yasuo Mori¹, Hideshi Kawakami², Shigenobu Nakamura², and Keiji Imoto¹

¹ Department of Information Physiology, National Institute for Physiological Sciences, Aichi 444-8585, Japan, and ² Third Department of Internal Medicine, Hiroshima University, School of Medicine, Hiroshima 734-8551, Japan

Spinocerebellar ataxia 6 (SCA6) is caused by expansion of a polyglutamine stretch, encoded by a CAG trinucleotide repeat, in the human P/Q-type Ca²⁺ channel _1A subunit. Although SCA6 shares common features with other neurodegenerative glutamine repeat disorders, the polyglutamine repeats in SCA6 are exceptionally small, ranging from 21 to 33. Because this size is too small to form insoluble aggregates that have been blamed for the cause of neurodegeneration, SCA6 is the disorder suitable for exploring the pathogenic mechanisms other than aggregate formation, whose universal role has been questioned. To characterize the pathogenic process of SCA6, we studied the effects of polyglutamine expansion on channel properties by analyzing currents flowing through the P/Q-type Ca²⁺ channels with an expanded stretch of 24, 30, or 40 polyglutamines, recombinantly expressed in baby hamster kidney cells. Whereas the Ca²⁺ channels with 24 polyglutamines showed normal properties, the Ca²⁺ channels with 30 or 40 polyglutamines exhibited an 8 mV hyperpolarizing shift in the voltage dependence of inactivation, which considerably reduces the available channel population at a resting membrane potential. The results suggest that polyglutamine expansion in SCA6 leads to neuronal death and cerebellar atrophy through reduction in Ca²⁺ influx into Purkinje cells and other neurons. Besides the widely accepted notion that polyglutamine stretches exert toxic effects by forming aggregates, expanded polyglutamines directly alter functions of the affected gene product.

Key words: spinocerebellar ataxia 6 (SCA6); P/Q-type Ca²⁺ channel; CAG repeat expansion; polyglutamine repeat; recombinant expression; neuronal death

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Copyright © 1999 Society for Neuroscience  0270-6474/99/$05.00/0

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