Possible Involvement of Ubiquitin Ligase HRD1 Insolubilization in Amyloid β Generation

Endoplasmic reticulum (ER)-associated degradation (ERAD) selectively retro-transports and degrades unfolded proteins accumulated in the ER. We have demonstrated that the ubiquitin ligase HRD1 involved in ERAD was significantly decreased in the cerebral cortex of Alzheimer’s disease patients. Furthermore, the HRD1 level was negatively correlated with amyloid β (Aβ) production levels. Here we found that the HRD1 protein level decrease was due to its insolubilization. Moreover, these protein levels extracted from detergent insoluble fraction were positively correlated with those of SEL1L and Aβs (Aβ40 and Aβ42). Thus, the insolubilization-induced decrease in the HRD1 and SEL1L levels might involve in Aβ generation. ; This study was supported by Grants-in-Aid for Science Research (KAKENHI) 21790089, 21300142, and 20659013 from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by the Research Foundation for Pharmaceutical Sciences.