Light and electron microscopic characterization of the evolution of cellular pathology in HdhQ92 Huntington's disease knock-in mice.

Huntington's disease (HD) is a fatally progressive neurodegenerative disease that is characterized anatomically by the abnormal accumulation of fragments of mutant huntingtin protein, within the glia and neurons of the brain. Several genetic (transgenic and knock-in) animal models have been established to mimic human HD. None of these models represent all of the elements of the human disease, but they provide an opportunity to understand the processes of the disease and aid in the development of therapeutic strategies. In this study, the Hdh(Q92) mouse model of Huntington's disease was analysed at different time points across the lifespan of the animal. At 4 months of age, Hdh(Q92/Q92) mice showed dense nuclear staining and nuclear inclusions in the olfactory tubercle and striatum with the mutant N-terminal antibody S830. Widespread formation of mutant huntingtin aggregates in the neuronal nuclei and cytosol increased in number with age and disease progression. Electron microscopy revealed that at 14 and at 21 months of age neurons showed the features of both necrotic and apoptotic cell death, such as irregular nuclear and cytoplasmic membranes, dark condensed nuclei, vacuolated cytoplasm, and swollen mitochondria. The spatial spread of NIIs progressed along the anterior-posterior and ventral-dorsal planes. Our detailed analyses of the Hdh(Q92) mouse line demonstrated a progressive and marked early focal striatal pathology with later widespread neuronal changes, including cellular degeneration, mutant protein aggregation and inclusion formation. We have demonstrated that the distribution of intra- and extra nuclear inclusions in this animal model expresses many features similar to the human pathology.