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Description:
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Mutations of the á1A 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 . |