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.
| Identifer | oai:union.ndltd.org:tamu.edu/oai:repository.tamu.edu:1969.1/3321 |
| Date | 12 April 2006 |
| Creators | Frank-Cannon, Tamy Catherine |
| Contributors | Abbott, Louise C |
| Publisher | Texas A&M University |
| Source Sets | Texas A and M University |
| Language | en_US |
| Detected Language | English |
| Type | Book, Thesis, Electronic Dissertation, text |
| Format | 4195733 bytes, electronic, application/pdf, born digital |
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