Direct alteration of the P/Q-type Ca2+ channel property by polyglutamine expansion in spinocerebellar ataxia 6.
Spinocerebellar ataxia 6 (SCA6) is caused by expansion of a polyglutamine stretch, encoded by a CAG trinucleotide repeat, in the human P/Q-type Ca(2+) channel alpha(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 Ca(2+) channels with an expanded stretch of 24, 30, or 40 polyglutamines, recombinantly expressed in baby hamster kidney cells. Whereas the Ca(2+) channels with </=24 polyglutamines showed normal properties, the Ca(2+) 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 Ca(2+) 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.
Matsuyama
Z
Z
Department of Information Physiology, National Institute for Physiological Sciences, Aichi 444-8585, Japan.
Wakamori
M
M
Mori
Y
Y
Kawakami
H
H
Nakamura
S
S
Imoto
K
K
D000818:Animals; D017209:Apoptosis; D020865:Calcium Channels, P-Type / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D020907:Calcium Channels, Q-Type / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D008564:Membrane Potentials; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000378:metabolism
D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D010455:Peptides; D011994:Recombinant Proteins; C097188:polyglutamine