[Molecular pharmacological studies on the protection mechanism against endoplasmic reticulum stress-induced neurodegenerative disease].

Endoplasmic reticulum (ER)-associated degradation (ERAD) is a mechanism against ER stress, wherein unfolded proteins accumulated in the ER are transported to the cytosol for degradation by the ubiquitin-proteasome system. 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, leads to ER stress and apoptosis. We have 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 showed 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 levels significantly decreased in the cerebral cortex of Alzheimer's disease patients, possibly because of its insolubilization. 4-phenylbutyrate (4-PBA) has been demonstrated to restore normal trafficking and activity of mutant proteins by acting as a chemical chaperone. We demonstrated that 4-PBA possesses chaperone activity in vitro, and this prevents protein aggregation. Furthermore, we revealed that 4-PBA attenuates the activation of ER stress responses and neuronal cell death, suggesting that HRD1 decreases unfolded protein accumulation in the ER. In addition, 4-PBA restores the normal expression of Pael-R protein and suppresses Pael-R-induced ER stress. Therefore, 4-PBA is a potential candidate for use in the pharmacotherapy of several neurodegenerative diseases linked to ER stress.