Neurology
Professor

• Profile

  I have been studying the pathogenesis of polyglutamine diseases and trying to develop treatments for 13 years. Neurodegenerative disorders including polyglutamine diseases, amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer disease are featured by progressive dysfunction and death of cells in selected areas in the nervous system. Much progress has been made in understanding the mechanisms of these diseases, effective treatments have not yet been established. One of these is spinal and bulbar muscular atrophy (SBMA), characterized by premature muscular exhaustion, progressive muscular weakness, atrophy, and fasciculation in bulbar and limb muscles. In SBMA, a polymorphic CAG repeat with 14-32 CAGs expands to 40-62 CAGs in the first exon of the androgen receptor (AR) gene. We have already examined several therapeutic approaches in a SBMA mouse model. As a consequence, we confirmed that castration and leuprorelin, a lutenizing hormone-releasing hormone agonist that reduces testosterone release from the testis, significantly rescued motor dysfunction and nuclear accumulation of mutant AR in male transgenic mice. Although this hormonal therapy was effective, it poses the unavoidable difficulty of severe sexual dysfunction. Most regrettably, this therapy cannot be applied to other polyQ diseases. Therefore, we have been trying to develop another treatments, such as stimulating the function of molecular chaperones and ubiquitin proteasome system that detoxicate and degrade abnormal proteins.
  Heat shock proteins (HSPs), which function mainly as molecular chaperones, play an important role in the folding and quality control of proteins. The histopathologic hallmark of neurodegenerative diseases is accumulation and/or inclusions of the disease-causing proteins in residual neurons in targeted regions of the nervous system. The inclusions combine with many components of molecular chaperone pathways and ubiquitin-proteasome, raising the possibility that misfolding and altered degradation of mutant proteins may be involved in the pathogenesis of neurodegenerative diseases. Overexpression of HSPs reduced the number and size of inclusions and accumulation of disease-causing proteins, and ameliorated the phenotypes in neuronal cell and mouse disease models. Hsp70 over-expression also enhanced degradation of polyglutamine-expanded proteins via its interaction with the UPS. CHIP (carboxyl terminus of Hsc70-interacting protein) might be one such coupling factor between the Hsp70 chaperone system and the machinery responsible for degrading mutant proteins. When CHIP was over-expressed, the motor and pathological phenotypes were markedly ameliorated, and this amelioration was correlated with the reduction of monomeric mutant AR and mutant AR protein complexes in the SBMA model. We also demonstrated that Hsp90 inhibitors selectively degraded the mutant AR, and inhibited neuronal nuclear accumulation of the mutant AR and significantly ameliorates motor phenotypes of the SBMA model mouse. Elucidation of its pathophysiology using animal models has led to the development of disease-modifying drugs, i.e., Hsp90 inhibitor and Hsp inducer, which inhibit the pathogenic process of neuronal degeneration. These findings may provide the basis for development of an HSP-related therapy for neurodegenerative diseases. But it is necessary to develop more highly specific strong therapies. The goal of my research is to establish effective treatments of these diseases.