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Title: Investigation of the mechanisms underlying phenotype development and neurodegeneration in a transgenic mouse model of Huntington's disease
Author: Hickey, M. A.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2001
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The R6/2 transgenic mouse model of HD displays a progressive neurological phenotype and motor and cognitive signs, comparable with signs and symptoms associated with HD. Experiments showed that R6/2 mice exhibited decreased response to dopaminergic locomotor stimulants with age. Chronic administration of L-DOPA significantly improved some aspects of the R6/2 neurological phenotype, such as hindlimb grooming and hypoactivity. However, it also caused deterioration in rotarod performance and in survival. These results suggested that decreased DA levels contributed to phenotype development and the progressive motor abnormalities seen in R6/2 mice. Similar changes may contribute to disease progression in HD. 3-Nitropropionic acid is a metabolic inhibitor used in the generation of neurochemical animal models of HD. Experiments showed that the frequency of 3-NP-induced striatal lesions in chronic 3-NP-treated mice was reduced in R6/2 mice. If, as has been suggested, energy impairment underlies neurotoxicity in HD, R6/2 mice would be expected to exhibit increased vulnerability to 3-NP. Other factors including mortality rates, rotarod performance, body weight profiles and SDH inhibition were similar between 3-NP-treated WT and R6/2 mice. These data question the involvement of energy impairment in early HD and suggest that R6/2 mice were protected from 3-NP-induced striatal toxicity. Further experiments were carried out to investigate if R6/2 mice were protected against neurotoxins with a mechanism of action different to 3-NP.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available