Possible Involvement of Ubiquitin Ligase HRD1 Insolubilization in Amyloid .BETA. Generation

Abstract

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.Key words Alzheimer's disease; amyloid β; HRD1; endoplasmic reticulum stress; SEL1L; insolubilization Alzheimer's disease (AD) is a progressive neurodegenerative disease of unknown etiology. Accumulation of amyloid β (Aβ) plaques and neurofibrillary tangles are the well-known neuropathological hallmarks of AD.1) The toxic Aβ peptides, Aβ40 and Aβ42, are generated from amyloid precursor protein (APP) via sequential proteolytic cleavages by β-secretase (BACE1) and γ-secretase complexes.2) APP is a type-I transmembrane glycoprotein, which is folded and N-glycosylated in the endoplasmic reticulum (ER) and is subsequently transported to the Golgi complex for further maturation.The ER is involved in the following several cellular functions: (i) membrane and secretory protein folding, posttranslational modification, and transport to the Golgi complex; (ii) maintenance of intracellular calcium homeostasis; (iii) synthesis of lipids and sterols; and (iv) regulation of cellular survival through the unfolded protein response (UPR) transducers, such as IRE1, ATF6, and PERK. Impairment of these processes causes an accumulation of unfolded proteins in the ER lumen, which is termed ER stress. ER stress activates the UPR pathways such as translational arrest, induction of ER chaperone, and ER-associated degradation (ERAD).3) ERAD pathways act as a defense mechanism against ER stress. In this pathway, ERAD targets are selected by a protein quality control mechanism within the ER lumen, subsequently removed by retrograde transport from the ER to the cytosol, and finally degraded by the ubiquitin-proteasome system. 4,5) Recent studies have shown an involvement of ER stress and dysfunction of ERAD pathway in AD. 6,7) In previous studies, we identified and characterized a human homolog of yeast Hrd1p/Der3p (HRD1) and Hrd3p (SEL1L). HRD1 has an E3 ubiquitin ligase activity and it colocalizes and forms a complex with its stabilizing factor SEL1L in the cerebral nerve. Furthermore, HRD1 is expressed as a result of ER stress and protects against ER stress-induced apoptosis. 5,[8][9][10][11][12] We recently found that HRD1 promoted the ubiquitination and degradation of APP in ERAD pathway, resulting in decreased Aβ production. On the other hand, suppression of HRD1 expression caused an accumulation of APP and an increase in Aβ lev...

Relationship between amyloid-beta and the ubiquitin–proteasome system in Alzheimer’s disease

“…The results suggest that the decrease in HRD1 levels in AD is a result of its insolubilization, which may be involved in Abeta generation. 33 Insolubilization of HRD1 protein causes dysfunction of HRD1, and this dysfunction results in increased Abeta levels. It is also reported that HRD1 promotes APP ubiquitination and degradation, resulting in decreased generation of Abeta.…”

Genetic and Epigenetic Mechanisms in Down Syndrome Brain

“…Beta amyloid could regulate synaptic protein degradation and function through ubiquitin pathway [136,137]. Moreover, several E3 ubiquitin ligases have been shown to promote APP degradation [138,139]. Additionally, HSA21 located genes AIRE and UBE2G2 are directly involved in the ubiquitin pathway and could contribute to the phenotype.…”

Effects of Oxidative Stress on the Solubility of HRD1, a Ubiquitin Ligase Implicated in Alzheimer’s Disease

“…In addition, we found that AD-affected neurons are under ER stress and, a significant decrease in HRD1 levels in the NP-40-soluble fraction was observed in the cerebral cortex of AD patients [2], which negatively correlated with Aβ accumulation levels in the human cerebral cortex [24]. Furthermore, we found an increase in the HRD1 levels in the NP-40-insoluble fraction, suggesting protein insolubilization [25]. Because the mechanism(s) underlying the change in HRD1 solubility are unclear, we have investigated the possible roles of AD-related molecules and stresses, such as Aβ, tau, ER stress, and oxidative stress.…”