Cerebellar Purkinje cell death in the P/Q -type voltage-gated calcium ion channel mutant mouse, leaner

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Title: Cerebellar Purkinje cell death in the P/Q -type voltage-gated calcium ion channel mutant mouse, leaner
Author: Frank-Cannon, Tamy Catherine
Abstract: Mutations of the ? ?1A subunit of P /Q -type voltage -gated calcium channels are responsible for several inherited disorders affecting humans , including familial hemiplegic migraine , episodic ataxia type 2 and spinocerebellar ataxia type 6 . These disorders include phenotypes such as a progressive cerebellar atrophy and ataxia . The leaner mouse also carries a mutation in the alpha (1A ) subunit of P /Q -type voltage -gated calcium channels , which results in a severe cerebellar atrophy and ataxia . The leaner mutation causes reduced calcium ion influx upon activation of P /Q -type voltage -gated calcium channels . This disrupts calcium homeostasis and leads to a loss of cerebellar neurons , including cerebellar Purkinje cells . Because of its similarities with human P /Qtype voltage -gated calcium channel mutations , leaner mouse has served as a model for these disorders to aid our understanding of calcium channel function and neurodegeneration associated with calcium channel dysfunction . The aims of this dissertation were : (1 ) to precisely define the timing and spatial pattern of leaner Purkinje cell death and (2 ) to assess the role of caspases and specifically of caspase 3 in directing leaner Purkinje cell death . We used the mechanism independent marker for cell death Fluoro -Jade and demonstrated the leaner Purkinje cell death begins around postnatal day 25 and peaks at postnatal day 40 to 50 . Based on this temporal pattern of Purkinje cell death we then investigated the role of caspases in leaner Purkinje cell death . These studies showed that caspase 3 is specifically activated in dying leaner cerebellar Purkinje cells . In addition , in vitro inhibition of caspase 3 activity partially rescued leaner Purkinje cells . Further investigation revealed that caspase 3 activation may be working together with or in response to macroautophagy . This study also indicated a potential role for mitochondrial signaling , demonstrated by the loss of mitochondrial membrane potential in leaner cerebellar Purkinje cells . However , our study revealed that if the loss of mitochondrial membrane potential is associated with leaner Purkinje cell death , this process is not mediated by the mitochondrial protein cytochrome C .
URI: http : / /hdl .handle .net /1969 .1 /3321
Date: 2006-04-12

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Cerebellar Purkinje cell death in the P/Q -type voltage-gated calcium ion channel mutant mouse, leaner. Available electronically from http : / /hdl .handle .net /1969 .1 /3321 .

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