Neuronal atrophy and synaptic alteration in a mouse model of dentatorubral-pallidoluysian atrophy.

Dentatorubral-pallidoluysian atrophy (DRPLA) is a hereditary spinocerebellar degeneration caused by expansion of a CAG repeat in the disease protein. Despite the restricted and stable brain lesions, DRPLA patients show a variety of clinical symptoms and the brain exhibits generalized atrophy. In previous studies of DRPLA, we proposed that intranuclear diffuse accumulation of the mutant protein is a significant pathological feature of neurons, and that the variable prevalence of this pathology may be relevant to the variation of symptoms observed in patients with different repeat sizes. In this study, to elucidate the pathogenesis of the brain atrophy in DRPLA, we conducted morphological and statistical analyses of neurons affected by the polyglutamine pathology in DRPLA transgenic (Tg) mice with 129 polyglutamine stretches. Golgi-impregnated pyramidal neurons in cerebral cortical layer V of 15-week-old Tg mice showed significant atrophy of the perikarya and dendrites. Dendritic spines were decreased in number and size, and showed a change in morphology resulting in dominance of stubby spines. Interestingly, dendritic arborization was preserved. Electron microscopy revealed that axons in the pyramis and corpus callosum were also atrophic. The number of axonal microtubules was preserved; however, the inter-microtubule spacing was significantly decreased. In the neuropil of cerebral cortical layers II and III, atrophy of the pre-synaptic areas and lengths of the post-synaptic density was detected, but synaptic vesicle diameter was preserved. These results suggest that neuronal atrophy is an essential feature of the cell pathology in DRPLA and that this is closely related to polyglutamine pathogenesis and development of the clinical phenotype.