著者

金子 雅幸

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.136, no.6, pp.805-809, 2016-06-01 (Released:2016-06-01)

参考文献数

26

被引用文献数

2 6

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Studies on endoplasmic reticulum (ER)-associated degradation (ERAD), in which unfolded proteins accumulated in the ER are selectively transported to the cytosol for degradation by the ubiquitin-proteasome system, have been focused on molecular mechanisms in yeast. In human, disruption of the ER quality control system causes various diseases, such as neurodegenerative disease, lifestyle disease, and cancer. However, there are many ERAD genes with unknown physiological and pathological functions. We identified the novel ubiquitin ligase HRD1 involved in ERAD. HRD1 is expressed in brain neurons and protects against ER stress-induced apoptosis. In familial Parkinson's disease, accumulation of Parkin-associated endothelin receptor-like receptor (Pael-R), a substrate of ubiquitin ligase Parkin involved in ERAD, causes ER stress and apoptosis. We demonstrated that HRD1 promotes ubiquitination and degradation of Pael-R and suppresses ER stress and apoptosis induced by Pael-R. Amyloid precursor protein (APP) is processed into amyloid β (Aβ) in Alzheimer's disease. We found that HRD1 promotes APP ubiquitination and degradation, resulting in decreased generation of Aβ. Furthermore, suppression of HRD1 expression causes APP accumulation and Aβ generation associated with ER stress and apoptosis. Interestingly, HRD1 protein levels significantly decreased in the cerebral cortex of Alzheimer's disease patients, possibly because of its insolubilization. We demonstrated that HRD1 protein was insolubilized by oxidative stress, resulting in the accumulation of HRD1 into the aggresome. In conclusion, oxidative stress-induced HRD1 insolubilization might be involved in a vicious cycle of increased Aβ production and Aβ-induced oxidative stress in Alzheimer's disease pathogenesis.

著者

野村 靖幸 大熊 康修 高橋 良輔 金子 雅幸 友部 浩二 篠塚 達雄 出雲 信夫 殿岡 啓子 浜名 洋

出版者

横浜薬科大学

雑誌

基盤研究(B)

巻号頁・発行日

2009

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HRD1は小胞体の変性タンパク質の分解を促進し、アルツハイマー病の原因タンパク質アミロイドβの前駆体APPを基質とする。本研究では、アルツハイマー病患者脳においてHRD1が酸化ストレスにより不溶化することで減少する可能性を示した。また、HRD1と類似した新規の酵素について、Aβの産生に関与するものを新たに見出した。さらに、タンパク質の凝集を阻害することで、パーキンソン病に関連したタンパク質の蓄積を防ぐ薬物を作成した。