Development of low-molecular-weight compound therapy for polyglutamine diseases

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In this study, we elucidated the pathophysiology of adult-onset motor neuron diseases, and developed pathogenesis-based therapy for them. Immunohistochemically using 1C2, an anti-polyglutamine antibody, demonstrated that diffuse nuclear accumulation of mutant AR was far more frequent and extensive than NIs being distributed in a wide array of CNS nuclei, and in more visceral organs than thus far believed. Furthermore, the extent of diffuse nuclear accumulation of mutant AR in spinal motor neurons was closely related to CAG repeat length. Thus, diffuse nuclear accumulation of mutant AR apparently is a cardinal pathogenesis underlying neurodegeneration in SBMA. The degree of mutant AR accumulation in scrotal skin epithelial cells tended to be correlated with that in the spinal motor neurons in autopsy specimens, and it was well correlated with CAG repeat length and inversely correlated with the motor functional scale. In a randomized double-blind trial, LHRH analog treatment inhibited mutant AR protein accumulation in the scrotal skin, reduced serum level of creatine kinase, and improved the swallowing function of SBMA patients.As for amyotrophic lateral sclerosis (ALS), we calrified that valosin-containing protein (VCP) directly binds to Dorfin, a protein modifying ALS pathogenesis, and that VCP ATPase activity profoundly contributes to the E3 activity of Dorfin. Using microarray technology combined with laser-captured microdissection, gene expression profiles of degenerating spinal motor neurons isolated from autopsied patients with sporadic ALS were examined. Downregulated genes included those associated with cytoskeleton/axonal transport, transcription, and cell surface antigens/receptors. In contrast, cell death-associated genes were mostly upregulated.