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dc.contributor.advisorAbbott, Louise C
dc.creatorFrank-Cannon, Tamy Catherine
dc.date.accessioned2006-04-12T16:06:31Z
dc.date.available2006-04-12T16:06:31Z
dc.date.created2005-12
dc.date.issued2006-04-12
dc.identifier.urihttps://hdl.handle.net/1969.1/3321
dc.description.abstractMutations 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.en
dc.format.extent4195733 bytesen
dc.format.mediumelectronicen
dc.format.mimetypeapplication/pdf
dc.language.isoen_US
dc.publisherTexas A&M University
dc.subjectcerebellumen
dc.subjectPurkinje cellen
dc.subjectcell deathen
dc.subjectneuronen
dc.subjectleaner mouseen
dc.titleCerebellar Purkinje cell death in the P/Q -type voltage-gated calcium ion channel mutant mouse, leaneren
dc.typeBooken
dc.typeThesisen
thesis.degree.departmentVeterinary Anatomy and Public Healthen
thesis.degree.disciplineVeterinary Anatomyen
thesis.degree.grantorTexas A&M Universityen
thesis.degree.nameDoctor of Philosophyen
thesis.degree.levelDoctoralen
dc.contributor.committeeMemberBurghardt, Robert C
dc.contributor.committeeMemberMiranda, Rajesh C
dc.contributor.committeeMemberTiffany-Castiglioni, Evelyn
dc.contributor.committeeMemberWelsh, C. Jane
dc.type.genreElectronic Dissertationen
dc.type.materialtexten
dc.format.digitalOriginborn digitalen


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