Loss of HRD1-mediated protein degradation causes amyloid precursor protein accumulation and amyloid-beta generation.
Endoplasmic reticulum-associated degradation (ERAD) is a system by which proteins accumulated in the endoplasmic reticulum (ER) are retrotranslocated to the cytosol and degraded by the ubiquitin-proteasome pathway. HRD1 is expressed in brain neurons and acts as an ERAD ubiquitin ligase. Amyloid precursor protein (APP) is processed into amyloid-beta peptides (Abetas) that form plaque deposits in the brains of Alzheimer's disease (AD) patients. We found significantly decreased HRD1 protein levels in the cerebral cortex of AD patients. HRD1 colocalized with APP in brain neurons and interacted with APP through the proline-rich region of HRD1. HRD1 promoted APP ubiquitination and degradation, resulting in decreased generation of Abeta. Furthermore, suppression of HRD1 expression induced APP accumulation that led to increased production of Abeta associated with ER stress. Immunohistochemical analysis revealed that suppression of HRD1 expression inhibited APP aggresome formation, resulting in apoptosis. In addition, we found that the ATF6- and XBP1-induced upregulation of ERAD led to APP degradation and reduced Abeta production. These results suggest that the breakdown of HRD1-mediated ERAD causes Abeta generation and ER stress, possibly linked to AD.
Kaneko
Masayuki
M
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Choshi, Chiba 288-0025, Japan.
Koike
Hiroshi
H
Saito
Ryo
R
Kitamura
Yoshihisa
Y
Okuma
Yasunobu
Y
Nomura
Yasuyuki
Y
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D018384:Oxidative Stress / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D054875:Ubiquitination
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases