Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant Ca _V 2.1 channels

Abstract

Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disorder caused by CAG repeat expansions within the voltage-gated calcium (CaV) 2.1 channel gene. It remains controversial whether the mutation exerts neurotoxicity by changing the function of CaV2.1 channel or through a gain-of-function mechanism associated with accumulation of the expanded polyglutamine protein.We generated three strains of knockin (KI) mice carrying normal, expanded, or hyperexpanded CAG repeat tracts in the Cacna1a locus. The mice expressing hyperexpanded polyglutamine (Sca6 84Q ) developed progressive motor impairment and aggregation of mutant CaV2.1 channels. Electrophysiological analysis of cerebellar Purkinje cells revealed similar Ca 2؉ channel current density among the three KI models. Neither voltage sensitivity of activation nor inactivation was altered in the Sca6 84Q neurons, suggesting that expanded CAG repeat per se does not affect the intrinsic electrophysiological properties of the channels. The pathogenesis of SCA6 is apparently linked to an age-dependent process accompanied by accumulation of mutant CaV2.1 channels.cerebullum ͉ polyglutamine ͉ P/Q-type voltage-dependent calcium channel

Development of Purkinje cell degeneration in a knockin mouse model reveals lysosomal involvement in the pathogenesis of SCA6

“…We analyzed the formation of NIs in the mutant PCs by immunohistochemistry using an A6RPT-polyQ Ab (10,11). This Ab reacts specifically with humanized Ca v 2.1 and revealed NI formation in the cytoplasm of the Sca6 84Q/84Q Purkinje neurons (10).…”

“…Recently, we generated a knockin (KI) mouse model (Sca6 84Q ) carrying an 84 CAG repeat tract in the mouse Cacna1a locus (10). Sca6 84Q mice recapitulate several features of SCA6, including the NI formation in PCs.…”

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

“…Studies in recombinant systems expressing CACNA1A cDNA from SCA6 patients suggest that the expanded CAG tract induces a hyperpolarizing shift in channel activation that could produce increased calcium load [45][46][47]. However, studies in Purkinje cells from the SCA6 knock-in mouse model have demonstrated no abnormalities in the intrinsic electrophysiologic properties of mutant Ca V 2.1 [13,48], although it should be noted that these data might not be able to reflect accurately abnormalities in dendritic calcium currents because of technical limitations associated with whole-cell somatic patch clamp recordings.…”

“…Studies of these models have yielded a surprising insight: the onset of apparent symptomatic impairment often precedes detectable neuropathology [10][11][12][13][14][15][16][17]. These results suggest that the cell loss observed in patient samples is representative of more advanced disease, and that reduced participation in an affected network due to neuronal loss may not be the only contributor to symptoms observed in patients.…”

Silver nanoparticle exposure induces rat motor dysfunction through decrease in expression of calcium channel protein in cerebellum

“…Loss-of-function CACNA1A gene mutants often showed early-onset motor dysfunction associated with distinct alterations of Ca 2+ channel properties, and impaired function of the cerebellar calcium channel Cav2.1 might have a central role in the pathogenesis of certain cases of ataxia (Mori et al, 2000;Wappl et al, 2002). Some types of ataxia, such as spinocerebellar ataxia type 6 were associated with decreased expression or impaired function of CACNA1A protein (Watase et al, 2008). In vivo and in vitro tests herein indicated the decrease in CACNA1A expression upon AgNPs treatment, showing the inhibition of Cav2.1 channel was involved in AgNPs-mediated cerebellar ataxia-like neurobehavior.…”