HD Insights™

H D I N S I G H T S HD Research Around the World: Japan Past, Present, and Future By: Hitoshi Okazawa, MD, PhD Huntington disease (HD) is rare in Japan. Its incidence is one-tenth of that observed in western countries, and as a result, the number of researchers studying HD in Japan is relatively low. Dr. Ichiro Kanazawa, former chair of the Department of Neurology at the University of Tokyo, was the first to initiate research on the molecular genetics and biology of HD in Japan. After Gusella and colleagues identified the HD causative gene in 1993, Dr. Kanazawa and Dr. Nobuyuki Nukina and colleagues used immunohistochemistry and western blot techniques to generate a polyclonal antibody against the expected mutant protein (mHtt), and confirmed the difference in length of the polyglutamine repeat sequence in mHtt compared to Htt, and its expression in the brain1. When post-genome research on HD started, Nukina discovered the involvement of the heat shock protein 40 family (Hsp40) and heat shock protein 70 family (Hsp70) in the pathogenesis of HD2. He developed a unique therapeutic approach based on selective autophagy3, and discovered the regulation of selective autophagy via the phosphorylation of p624. My group studies the functional side of mHtt. The polyglutamine repeat sequence is important for transcription-related proteins. Oct-3/ Oct-4, an octamer transcription factor, is now recognized as the most important transcription factor for embryonic stem cells and induced pluripotent stem cells5. Many transcription factors possess these polyglutamine sequences, and the tract sequence has been suggested as a motif for protein–protein interaction. Using this knowledge, my group identified a novel mediator of polyglutamine diseases, namely polyglutamine-binding protein-16,7, which the European Consortium of Xlinked Mental Retardation subsequently recognized as the cause of a spectrum of mental retardations8. Much of the current HD research in Japan is focused on therapy. Therapeutic research trends include the activation of selective autophagy; inhibition of mHtt; functional recovery of target physiological proteins; and use of induced pluripotent stem cells. Some of these approaches have reached the preclinical stage. Dr. Nukinaʼs group has identified that trehalose has a therapeutic effect in HD9. Dr. Nagai (National Center of Neurology and Psychiatry) and colleagues discovered that polyglutamine-binding peptide-1 (an artificial peptide distinct from the endogenous polyglutamine-binding protein-1 referred to above) showed a protective effect against aggregation10,11. Meanwhile, my group has used genomics and proteomics to screen pathological mediators of HD. Using genomics, we determined that Hsp70 plays a critical role in neuron subtypespecific vulnerability12. Using proteomics, we found that highmobility group protein B, a DNA architectural protein, is involved in HD pathology13. In collaboration with Dr. Erich Wanker (Max-Delbrück Center for Molecular Medicine, Germany) and by using an interactomics approach, we discovered that Ku70, a DNA damage repair protein, plays a role in HD pathology14. More recently, we discovered that DNA damage repair by VCP/TERA/p97 is involved in the pathology of many polyglutamine diseases15. These targets of mHtt are functionally disturbed in HD, and the foci of their functions cluster around transcription and DNA damage repair, although other functions of these molecules, such as autophagy, may also be relevant. Functional rescue of these molecular targets has proved very successful in mice models of HD. Viral vector-mediated supplementation of high-mobility group protein B1, Ku70, and some other molecules has been very successful in mice model treatment for HD, spinocerebellar ataxia type 1, and other diseases. Details of such research will be published in the future. If you are interested in contributing a piece that highlights research in your part of the world, please contact us at editor@hdinsights.org. HD Insights, Vol. 4 Copyright © Huntington Study Group 2013. All rights reserved. 7

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