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Title: Mitochondrial abnormalities in PrP-null mice and Mecp2-null mice
Author: Paterson, Andrew William James
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2007
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Evidence of a mitochondrial abnormality in PrP-null mice was sought by extensive assessment of the morphological and functional characteristics of isolated brain mitochondria. Study of isolated mitochondrial suspensions by electron microscopy revealed that PrP-null mitochondria were larger and, when cristae density was quantitatively measured using a novel technique, to have a reduced cristae density when compared to controls. A significant increase in respiratory capacity was detected in PrP-null mitochondria when metabolising Complex I substrates, but not when electrons entered downstream of complex 1. This implicates Complex 1 as a site for pathological change. As recent studies of the Mecp2-null mouse model of Rett syndrome detected increased transcription of Uqcrc1 (a core subunit of Complex III), mitochondrial morphology and respiration were studied in Mecp2-null mice. Whilst electron microscopy did not reveal any gross alterations in mitochondrial size or cristae density, respiration measurements revealed a severe phenotype in symptomatic, but not presymptomatic, Mecp2-null mice. Mitochondrial coupling was considerably reduced in isolated brain mitochondria from Mecp2-null mice indicating reduced mitochondrial efficiency. This effect was accompanied by an increase in respiratory capacity through Complex III. In order to determine if the overexpression of Uqcrc1 was causative in the production of the observed increase in respiratory capacity, the respiration rates of N2A cells overexpressing Uqcrc1 were measured. As transfected N2A cells showed significantly increased respiration rates through Complex III, the up-regulation of Uqcrc1 may be causative in producing the respiratory capacity increase observed in the animal model. These results enhance the evidence for dysfunctional mitochondria in both PrP-null and Mecp2-null mouse models and are discussed in relation to other investigations of prion disease, Rett syndrome and other models of neurodegenerative disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available