Loss of HRD1-Mediated Protein Degradation Causes Amyloid Precursor Protein Accumulation and Amyloid-β Generation

@article{Kaneko2010LossOH,
  title={Loss of HRD1-Mediated Protein Degradation Causes Amyloid Precursor Protein Accumulation and Amyloid-$\beta$ Generation},
  author={Masayuki Kaneko and Hiroshi Koike and Ryo Saito and Yoshihisa Kitamura and Yasunobu Okuma and Yasuyuki Nomura},
  journal={The Journal of Neuroscience},
  year={2010},
  volume={30},
  pages={3924 - 3932}
}
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-β peptides (Aβs) that form plaque deposits in the brains of Alzheimer's disease (AD) patients. We found significantly decreased HRD1 protein levels in… 
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Correlation between decrease in protein levels of ubiquitin ligase HRD1 and amyloid-beta production.
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The relationship between HRD1 protein levels and Abeta production was negatively correlated with the Abeta level, suggesting the possible involvement of HRD2 in Abeta generation and endoplasmic reticulum-associated degradation.
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EDEM1 is a novel regulator of APP metabolism through ERAD, and overproduction of EDEM1 results in decreased Aβ40 and Aβ42 secretion and increased in cells with downregulated EDem1.
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HRD1 protein was insolubilized by oxidative stress, resulting in the accumulation of HRD1 into the aggresome, which might be involved in a vicious cycle of increased Aβ production and Aβ-induced oxidative stress in Alzheimer's disease pathogenesis.
FBL2 Regulates Amyloid Precursor Protein (APP) Metabolism by Promoting Ubiquitination-Dependent APP Degradation and Inhibition of APP Endocytosis
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It is demonstrated that the F-box and leucine rich repeat protein2 (FBL2), a component of the E3 ubiquitin ligase complex, regulates amyloid precursor protein (APP) metabolism through APP ubiquitination.
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It is shown that HRD1 protein was insolubilized by oxidative stress but not by other Alzheimer’s disease-related molecules and stressors, such as amyloid β, tau, and endoplasmic reticulum stress.
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It is demonstrated that the ubiquitin ligase HRD1 involved in ERAD was significantly decreased in the cerebral cortex of Alzheimer's disease patients and it was found that theHRD1 protein level decrease was due to its insolubilization.
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The data suggest that geniposide might be benefit to re-establish proteostasis by enhancing the UPR to decrease the load of APP in neurons challenged by high glucose.
Molecular approaches to the treatment, prophylaxis, and diagnosis of Alzheimer's disease: possible involvement of HRD1, a novel molecule related to endoplasmic reticulum stress, in Alzheimer's disease.
TLDR
The novel ubiquitin ligase HRD1, which is involved in ERAD, was cloned and it was shown thatHRD1 promoted amyloid precursor protein (APP) ubiquitination and degradation, resulting in decreased generation ofAmyloid β (Aβ) and suppression of HRD 1 expression caused APP accumulation and promoted Aβ generation associated with ER stress and apoptosis.
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