Neurology

1975

Graduated from Nagoya University School of Medicine (MD)

1981

Completed Nagoya University Graduate School of Medicine (PhD)

1981-1991

Lecturer, Aichi Medical University

1982-1983

Research Fellow, University of Pennsylvania

1983-1984

Assistant Professor, University of Pennsylvania

1991-1995

Associate Professor, Aichi Medical University

1995-2000

Professor, Nagoya University School of Medicine

2000-present

Professor, Nagoya University Graduate School of Medicine

Elucidation of pathogenesis and therapy development for neurodegenerative disorders

Overcoming neurodegenerative disorders is one of the high-priority medical issues in the 21st century. Until now, neurodegenerative disorders have been predominantly treated by replacement therapy supplying deficient substances in the central nervous system e.g. l-dopa therapy in Parkinson’s disease. Since such therapy does not prevent neurodegeneration per se, its efficacy is very limited. We have been challenging development of molecular mechanism-based therapy preventing neurodegeneration through research on motor neuron diseases.

Amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA) are adult-onset motor neuron diseases which represent neurodegenerative disorders. So far, we have aimed at elucidation of pathogenesis and therapy development for these intractable diseases.

The cause of SBMA is expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract within the first exon of the androgen receptor (AR) gene. We have clarified that ligand-dependent nuclear accumulation of the mutant AR has an important implication in the pathogenesis of neurodegeneration. We have developed transgenic mouse model carrying full-length human AR with expanded polyglutamine and found that it demonstrates sexual difference of phenotypes. The neuromuscular phenotypes of the SBMA mice are reversed by castration or leuprorelin, an LHRH agonist that reduces testosterone release from the testis. They inhibit nuclear accumulation of the mutant AR, resulting in rescue of motor dysfunction in the male transgenic mice.

Now these insights are being translated into the development of disease-modifying therapy for SBMA. In a preliminary clinical trial, leuprorelin has been shown to inhibit nuclear accumulation of the mutant AR in the scrotal skin, reduce serum creatine kinase level, and stabilize progression of motor impairment in the patients with SBMA.

Also we have successfully developed some other molecular-targeted therapies for SBMA. Treatment with 17-allylamino geldanamycin (17-AAG), a potent Hsp90 inhibitor, facilitates proteasomal degradation of the mutant AR, leading to marked amelioration of motor impairment in the mouse model of SBMA. Interestingly, many of the therapeutic targets we have identified are also involved in the pathogenesis of cancer, and leuprorelin and 17-AAG are known as therapeutic agents for cancer.

Thus, we have achieved a great success in this field, and application of molecular-targeted therapy to human neurodegenerative disorders is now within reach of us.

Meanwhile, we have made a great contribution to revealing the pathogenesis of ALS, which is more devastating than SBMA. Through the gene expression analysis, we have successfully cloned a novel gene designated “dorfin,” which mediates ubiquitin ligase (E3) activity. Interestingly, dorfin is predominantly localized and overexpressed in the ubiquitinated neuronal hyaline inclusion bodies found in the motor neurons of sporadic ALS (SALS) patients and model mice. We have clarified its protective role in the pathogenesis of ALS via the ubiquitylation and degradation of its substrates.

Furthermore, we have successfully revealed motor neuron-specific gene expression profile in SALS using microarray technology combined with laser-captured microdissection (LCM). Based on the results of gene expression profile, we have launched the project for creating sporadic ALS models by reproduction of early gene expression changes in cell culture and animal.

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2. Okada Y et al. Spatio-temporal recapitulation of central nervous system development by murine ES cell-derived neural stem/progenitor cells. Stem Cells in press (2008)
3. Yang Z et al. ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor. Nature Med. 13: 348-353 (2007)
4. Adachi H et al. CHIP overexpression reduces mutant androgen receptor protein and ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model. J. Neurosci. 27: 5115-5126 (2007)
5. Katsumo M et al. Reversible disruption of dynactin 1-mediated retrograde axonal transport in polyglutamine-induced motor neuron degeneration. J. Neurosci. 26: 12106-12117 (2006)
6. Banno H et al. Mutant androgen receptor accumulation in spinal and bulbar muscular atrophy scrotal skin: a pathogenic marker. Ann. Neurol. 59: 520-526 (2006)
7. Waza M et al. 17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration. Nature Med. 11: 1088-1095 (2005)
8. Katsuno M et al. Pharmacological induction of heat shock proteins alleviates polyglutamine-mediated motor neuron disease. Proc. Natl. Acad. Sci. USA. 102: 16801-16806 (2005)
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Toshihiko Tokizane Memorial Award　2005
Chunichi Culture Award　2007