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Omi / HtrA2 is relevant to the selective vulnerability of striatal neurons in Huntington’s disease

Authors

  • Reina Inagaki,

    1. Department of Neuropathology, Medical Research Institute and 21st Century Center of Excellence Program (COE) for Brain Integration and Its Disorders, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
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    • *

      These authors contributed equally to this work.

  • Kazuhiko Tagawa,

    1. Department of Neuropathology, Medical Research Institute and 21st Century Center of Excellence Program (COE) for Brain Integration and Its Disorders, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
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    • *

      These authors contributed equally to this work.

  • Mei-Ling Qi,

    1. Department of Neuropathology, Medical Research Institute and 21st Century Center of Excellence Program (COE) for Brain Integration and Its Disorders, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
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  • Yasushi Enokido,

    1. Department of Neuropathology, Medical Research Institute and 21st Century Center of Excellence Program (COE) for Brain Integration and Its Disorders, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
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  • Hikaru Ito,

    1. Department of Neuropathology, Medical Research Institute and 21st Century Center of Excellence Program (COE) for Brain Integration and Its Disorders, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
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  • Takuya Tamura,

    1. Department of Neuropathology, Medical Research Institute and 21st Century Center of Excellence Program (COE) for Brain Integration and Its Disorders, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
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  • Shigeomi Shimizu,

    1. Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
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  • Kityomitsu Oyanagi,

    1. Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan
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  • Nobutaka Arai,

    1. Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan
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  • Ichiro Kanazawa,

    1. National Center for Neurology and Psychiatry, 4-1-1, Ogawa Higashi machi, Kodaira, Tokyo 187-8551, Japan
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  • Erich E Wanker,

    1. Neuroproteomics, Max-Delbrück Center for Molecular Medicine Berlin-Buch, Robert-Rössle-Str. 10,13092 Berlin, Germany
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  • Hitoshi Okazawa

    1. Department of Neuropathology, Medical Research Institute and 21st Century Center of Excellence Program (COE) for Brain Integration and Its Disorders, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
    2. Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan
    3. PRESTO, Japan Science and Technology Agency (JST), Tokyo, Japan
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Dr H. Okazawa, 1Department of Neuropathology, as above.
E-mail: okazawa-tky@umin.ac.jp

Abstract

Selective vulnerability of neurons is a critical feature of neurodegenerative diseases, but the underlying molecular mechanisms remain largely unknown. We here report that Omi/HtrA2, a mitochondrial protein regulating survival and apoptosis of cells, decreases selectively in striatal neurons that are most vulnerable to the Huntington’s disease (HD) pathology. In microarray analysis, Omi/HtrA2 was decreased under the expression of mutant huntingtin (htt) in striatal neurons but not in cortical or cerebellar neurons. Mutant ataxin-1 (Atx-1) did not affect Omi/HtrA2 in any type of neuron. Western blot analysis of primary neurons expressing mutant htt also confirmed the selective reduction of the Omi/HtrA2 protein. Immunohistochemistry with a mutant htt-transgenic mouse line and human HD brains confirmed reduction of Omi/HtrA2 in striatal neurons. Overexpression of Omi/HtrA2 by adenovirus vector reverted mutant htt-induced cell death in primary neurons. These results collectively suggest that the homeostatic but not proapoptotic function of Omi/HtrA2 is linked to selective vulnerability of striatal neurons in HD pathology.

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