Longitudinal characterisation of neuropathology in transgenic and knock-in Huntington's disease mouse lines

• Main Author: Bayram-Weston, Zubeyde
• Published: Cardiff University 2011
• Subjects: 616.8; QP Physiology
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.567157

The work presented in this thesis consists of 4 manuscripts, focussed on characterising the distribution of mutant huntingtin protein in transgenic and knock-in mouse models of Huntington’s disease. The mouse lines showed a different expression level of mutant huntingtin across the different time points. In the R6/1 mice, the inclusions were present and widespread from 3.5 weeks of age. In the YAC128 mice, inclusions were not present until 15 months of age, but then developed rapidly throughout the brain. In the HdhQ92 and HdhQ150 mice, intra nuclear inclusions (NIIs) were apparent at 10 and 5 months of age, respectively, and spread anterior to posterior and ventral-dorsal directions. In this thesis, the study has shown no increase in GFAP immunoactivity in the striatum of each mice line. However we detected a small increase in GFAP immunoactivity in the cortex of transgenic mouse models. With electron microscopy, we observed ultrastructural pathology with vacuolization, uneven cell membrane and degenerated mitochondria in these mouse lines along side with the presence of inclusions. Each mouse line showed different levels of degeneration such as YAC128 and HdhQ92 mice exhibited apoptitic neurons, whereas HdhQ150 mice has shown signs of necrosis. The results demonstrate that each of the mouse lines studied has a unique pattern of development of neuropathology. Inclusion formations may not be pathogenic per se, but may be representative of the dysfunctional neuronal populations that underpin the functional disturbances found in each of these mouse lines. Electron microscopy shows different cell death morphology in these mouse lines.