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Home  > Press Release  > “Impairment of DNA-repair by mutant Huntingtin is a major cause of neurodegenerative pathology in Huntington’s disease.”

“Impairment of DNA-repair by mutant Huntingtin is a major cause of neurodegenerative pathology in Huntington’s disease.”

Professor Hitoshi Okazawa
Department of Neuropathology,
Division of Pathophysiology,
Medical Research Institute

-Development of novel a therapeutic approach of Huntington’s disease by compensation with DNA-repair function.


Summary
A group in department of neuropathology, Medical Research Institute, Tokyo Medical and Dental University led by professor Hitoshi Okazawa has uncovered that a major mechanism underlying Huntington’s disease pathology is mediated by impairment of DNA-repair and this symptom could be significantly reversed by complementation with DNA-repair protein, Ku70. This work was supported by several research grants such as the Japan Science and Technology Agency (CREST) and the Ministry of Education, Culture, Sports, Science and Technology of Japan. This study has been published on-line in an international scientific Journal, The Journal of Cell Biology on May 4th, 2010.

Highlights
•There is no effective drug for Huntington’s disease, which is one of the popular neurodegenerative disorders.
•The study has uncovered that a major pathology in Huntington’s disease is mediated by impairment of DNA-repair protein, Ku70.
•The causative gene product, mutant Huntingtin inhibits DNA double strand break-repair through association with one of the DNA-repair components, Ku70.
•Complementation with Ku70 in the Huntington’s disease model mouse significantly improves the symptoms more than any other reports. This achievement is expected to be a fundamental of a future therapeutic approach for Huntington’s disease drug.

Research background
Huntington’s disease composes a major group of hereditary neurodegenerative disorders. The occurrence ratio of Huntington’s disease in Caucasian background is about 5-10 cases out of 100,000 in Europe, gathering much attention along with Alzheimer’s disease. The symptoms observed are such as dementia, movement impairment and depression finally ended up with death. This disease is the first example that molecular genetics had identified the causative gene in neurodegenerative disorder. The causative gene, Huntingtin was identified by a consortium organized by professor James Gusella, Harvard University in 1993. However, the molecular mechanism underlying the disease, such as function of Huntingtin protein and details in the process of neuronal cell defect caused by the mutated gene product remains to be elucidated extensively. There is no effective therapeutic strategy even in extending patient’s life span.

Research Summary
The study has uncovered that the pathology in Huntington’s disease is mediated by malfunction of DNA-repair protein, Ku70 and that complementation with Ku70 in the Huntington’s disease model mouse significantly prolongs the life span more than any other methods. The results obtained are: 1) The mutant Huntingtin protein associates with Ku70; 2) Through the association, it inhibits DNA-repair function in Ku70; 3) DNA damages and the signaling are increased in striatal neurons of the transgenic mouse, the knock-in mouse and human disease cases; 4) Overexpression of Ku70 in Huntington’s disease mouse model, R6/2 by crossing with Ku70-transgenic mouse decreases DNA damage, leading to expansion of life span.
This group has previously proposed that abnormality in DNA-repair is one of the new pathologies in polyglutamine diseases (Qi et al., Nat Cell Biol. 2007: JST press release; http//www.jst.go.jp/pr/announce/20070326/index.html). In addition, it is known that mutation in DNA-repair genes itself leads to other neurodegenerative diseases and that radiation by X-ray causes symptoms similar to neurodegenerative disease. These results collectively suggest that DNA-repair-related mechanism is one of the fundamental pathology in several neurodegenerative pathosignalings.


Figure
Soluble Huntingtin protein (Mutant Huntingtin) associates with Ku70 leading to inhibition of DNA-repair protein complex formation resulting in impairment of DNA repair and accumulation of DNA damage.


Significance
The study has uncovered that impairment of DNA-repair is a major pathological mechanism in Huntington’s disease and has identified the target molecule, Ku70. Furthermore, the study has found that complementation of functional Ku70 in Huntington’s disease mouse model significantly prolongs life span compared to any other methods. This achievement could be an idea for the novel therapeutic approaches for human neurodegenerative diseases including Huntington’s disease.

Contact

Hitoshi Okazawa, M.D., Ph.D.
Department of Neuropathology, Division of Pathophysiology, Medical Research Institute,
Tokyo Medical and Dental University
Phone: +81-3-5803-5847
Fax: +81-3-5803-5847
E-mail: okazawa.npat@mri.tmd.ac.jp