HD Research Around the World: Japan

Past, Present, and Future

japanBy: 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 subtype-specific vulnerability12. Using proteomics, we found that high-mobility 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.

DNA double strand break is increased in striatal neurons of human HD patients.14

DNA double strand break is increased in striatal neurons of human HD patients.14

Lifespan elongation by Ku70. Double transgenic mice have a 30% longer lifespan.14

Lifespan elongation by Ku70. Double transgenic mice have a 30% longer lifespan.14

 Colocalization of mutant huntingtin and Ku70 in astriatal neuron of R6/2 mouse.14

Colocalization of mutant huntingtin and Ku70 in astriatal neuron of R6/2 mouse.14











Moreover, mice models of HD treated with the above-mentioned genes have shown longer survival than other reported treatments. Due to limited social and financial support for HD research in Japan, HD research groups collaborate closely with each other and with research groups studying other neurodegenerative diseases. In order to advance HD research in Japan, there must be closer collaboration with researchers in countries that have a higher incidence of HD and consequent stronger support for HD research. International collaboration with pharmaceutical companies is also essential.

Dr. Okazawa would like to thank all friends around the world for their current and future support.


1 Yazawa I, Nukina N, Hashida H, et al. Abnormal gene product identified in hereditary dentatorubralpallidoluysian atrophy (DRPLA) brain. Nat Genet 1995 May; 10(1):99-103.

2 Jana NR, Tanaka M, Wang GH, et al. Polyglutamine lengthdependent interaction of Hsp40 and Hsp70 family chaperones with truncated N-

3 Bauer PO, Goswami A, Wong HK, et al. Harnessing chaperone-mediated autophagy for the selective degradation of mutant huntingtin protein. Nat Biotechnol 2010 Mar;28(3): 256-63. doi: 10.1038/nbt.1608. Epub 2010 Feb 28.

4 Matsumoto G, Wada K, Okuno M, et al. Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol Cell 2011 Oct;44(2):279-89.

5 Okamoto K, Okazawa H, Okuda A, et al. A novel octamer binding transcription factor is differentially expressed in mouse embryonic cells. Cell 1990 Feb;60(3):461-72.

6 Waragai M, Lammers CH, Takeuchi S, et al. PQBP-1, a novel polyglutamine tract-binding protein, inhibits transcription activation by Brn-2 and affects cell survival. Hum Mol Genet 1999 Jun; 8(6):977-87. 7 Okazawa H, Rich T, Chang A, et al. Interaction between mutant ataxin-1 and PQBP-1 affects transcription and cell death. Neuron 2002 May;34(5):701-13.

8 Kalscheuer VM, Freude K, Musante L, et al. Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation. Nat Genet. 2003 Dec; 35(4):313-5. Epub 2003 Nov 23.

9 Tanaka M, Machida Y, Niu S, et al. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med 2004 Feb;10(2):148-54.

10 Nagai Y, Tucker T, Ren H, et al. Inhibition of polyglutamine protein aggregation and cell death by novel peptides identified by phage display screening. J Biol Chem 2000 Apr; 275(14):10437-42.

11 Nagai Y, Fujikake N, Ohno K, et al. Prevention of polyglutamine oligomerization and neurodegeneration by the peptide inhibitor QBP1 in Drosophila. Hum Mol Genet 2003 Jun; 12(11):1253-9.

12 Tagawa K, Marubuchi S, Qi ML, et al. The induction levels of heat shock protein 70 differentiate the vulnerabilities to mutant huntingtin among neuronal subtypes. J Neurosci 2007 Jan; 27(4):868-80.

13 Qi ML, Tagawa K, Enokido Y, et al. Proteome analysis of soluble nuclear proteins reveals that HMGB1/2 suppress genotoxic stress in polyglutamine diseases. Nat Cell Biol 2007 Apr; 9(4):402-14.

14 Enokido Y, Tamura T, Ito H, et al. Mutant huntingtin impairs Ku70-mediated DNA repair. J Cell Biol 2010 May 3; 189(3):425-43.

15 Fujita K, Nakamura Y, Oka T, et al. A functional deficiency of TERA/VCP/p97 contributes to impaired DNA damage repair in multiple polyglutamine diseases. Nature Commun In press.