Investigating the functional consequences of expanded triplet repeat sequence in a mouse model of Huntington's Disease (HD)

Chen, Chiung-Mei (2002) Investigating the functional consequences of expanded triplet repeat sequence in a mouse model of Huntington's Disease (HD). PhD thesis, University of Glasgow.

Abstract

A PCR strategy showed that a number of total mtDNA molecules was significantly decreased (~30%) in the striatum (no reduction in the cortex and cerebellum) of 24-month old HD mice, but not a 15 months of age, when compared to wild-type mice, suggesting mtDNA depletion is a progressive rather than a developmental phenomenon.

In light of the ~30% reduction of total mtDNA in the striatum, expression levels of the mitochondrial DNA-encoded respiratory complex enzymes, cytochrome b(Cytb), cytochrome c oxidase I (COI) and cytochrome c oxidase II (COII) were investigated in different brain regions of HD mice. At ~25 months of age, there were no significant differences in mRNA levels of CoII and Cytb in any brain region (striatum, cortex and cerebellum) studied when compared to normal littermates. However, HD mice showed significantly decreased CO-I protein levels and marginally decreased CoI mRNA levels in the striatum.

Reduced levels of mtDNA may be caused by decreased replication of mtDNA or increased oxidative damage of mtDNA. Increased levels of 8-OHdG, a marker of increased oxidative stress, were detected in the dorsomedial, dorsolateral and ventromedial striatum, but not in the cortex of 24-month old HD mice providing direct evidence that increased oxidative stress specifically occurs in the striatum of HD mice. As no alterations in the mitochondrial transcription factor (mtTFA) in the striatum of HD mice could be detected, it is likely that mtDNA depletion in the HD mice is caused by increased levels of oxidative stress rather than decreased replication.

The results provide a basis for further studies investigating how mutant huntingtin causes increased levels of oxidative stress and for identifying novel therapeutic targets.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QH Natural history > QH301 Biology; Q Science > QH Natural history > QH426 Genetics
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences > Molecular Biosciences
• Supervisor's Name: Shelbourne, Peggy
• Date of Award: 2002
• Depositing User: Elaine Ballantyne
• Unique ID: glathesis:2002-2114
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 21 Sep 2010
• Last Modified: 10 Dec 2012 13:51
• URI: https://theses.gla.ac.uk/id/eprint/2114