2013 Fiscal Year Final Research Report
Effects of Oxidative Stress on the Solubility of HRD1, a Ubiquitin Ligase Implicated in Alzheimer's Disease.
| Project/Area Number |
23790095
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Biological pharmacy
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| Research Institution | Gifu Pharmaceutical University (2012-2013)
Chiba Institute of Science (2011) |
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Principal Investigator |
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| Project Period (FY) |
2011 – 2013
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| Keywords | 小胞体ストレス / ERAD / アルツハイマー病 / 酸化ストレス / 不溶化 / アミロイドβ / ユビキチンリガーゼ / HRD1 |
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| Research Abstract |
The E3 ubiquitin ligase HRD1 is found in the endoplasmic reticulum membrane (ER) of brain neurons and is involved in ER-associated degradation. We previously demonstrated that suppression of HRD1 expression in neurons causes accumulation of amyloid precursor protein, resulting in amyloid beta (Abeta) production associated with ER stress and apoptosis. Furthermore, HRD1 levels are significantly decreased in the cerebral cortex of Alzheimer's disease (AD) patients because of its insolubility. The mechanisms that affect HRD1 solubility are not well understood. We here show that HRD1 protein was insolubilized by oxidative stress. Furthermore, we reveal that modifications of HRD1 by 4-hydroxy-2-nonenal decreases HRD1 solubility and the oxidative stress led to the accumulation of HRD1 into the aggresome. Thus, oxidative stress-induced HRD1 insolubilization might be involved in a vicious cycle of increased Abeta production and Abeta-induced oxidative stress in AD pathogenesis.
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Author(s)
Kondo S, Hino SI, Saito A, Kanemoto S, Kawasaki N, Asada R, Izumi S, Iwamoto H, Oki M, Miyagi H, Kaneko M, Nomura Y, Urano F and Imaizumi K
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DOI
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