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
Endoplasmic reticulum (ER)-associated degradation (ERAD) is a protective mechanism against ER stress in which unfolded proteins accumulated in the ER are selectively transported to the cytosol for degradation by the ubiquitin–proteasome system. We cloned the novel ubiquitin ligase HRD1, which is inv...
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| Format: | Article |
| Language: | English |
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Elsevier
2012-01-01
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| Series: | Journal of Pharmacological Sciences |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1347861319305572 |
| _version_ | 1819153557671116800 |
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| author | Masayuki Kaneko Yasunobu Okuma Yasuyuki Nomura |
| author_facet | Masayuki Kaneko Yasunobu Okuma Yasuyuki Nomura |
| author_sort | Masayuki Kaneko |
| collection | DOAJ |
| description | Endoplasmic reticulum (ER)-associated degradation (ERAD) is a protective mechanism against ER stress in which unfolded proteins accumulated in the ER are selectively transported to the cytosol for degradation by the ubiquitin–proteasome system. We cloned the novel ubiquitin ligase HRD1, which is involved in ERAD, and showed that HRD1 promoted amyloid precursor protein (APP) ubiquitination and degradation, resulting in decreased generation of amyloid β (Aβ). In addition, suppression of HRD1 expression caused APP accumulation and promoted Aβ generation associated with ER stress and apoptosis. Interestingly, HRD1 levels were significantly decreased in the cerebral cortex of patients with Alzheimer’s disease (AD), and the brains of these patients experienced ER stress. Our recent study revealed that this decrease in HRD1 was due to its insolubilization; however, controversy persists about whether the decrease in HRD1 protein promotes Aβ generation or whether Aβ neurotoxicity causes the decrease in HRD1 protein levels. Here, we review current findings on the mechanism of HRD1 protein loss in the AD brain and the involvement of HRD1 in the pathogenesis of AD. Furthermore, we propose that HRD1 may be a target for novel AD therapeutics. Keywords:: Alzheimer’s disease, amyloid β, endoplasmic reticulum–associated degradation, HRD1, neurodegenerative disease |
| first_indexed | 2024-12-22T15:07:05Z |
| format | Article |
| id | doaj.art-53ba31a82fb940d59db9630d3585594f |
| institution | Directory Open Access Journal |
| issn | 1347-8613 |
| language | English |
| last_indexed | 2024-12-22T15:07:05Z |
| publishDate | 2012-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Pharmacological Sciences |
| spelling | doaj.art-53ba31a82fb940d59db9630d3585594f2022-12-21T18:21:58ZengElsevierJournal of Pharmacological Sciences1347-86132012-01-011183325330Molecular 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 DiseaseMasayuki Kaneko0Yasunobu Okuma1Yasuyuki Nomura2Department of Pharmacology, Faculty of Pharmaceutical Sciences, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi 288-0025, Japan; Corresponding author. mkaneko@cis.ac.jpDepartment of Pharmacology, Faculty of Pharmaceutical Sciences, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi 288-0025, JapanLaboratory of Pharmacotherapeutics, Yokohama College of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama 245-0066, JapanEndoplasmic reticulum (ER)-associated degradation (ERAD) is a protective mechanism against ER stress in which unfolded proteins accumulated in the ER are selectively transported to the cytosol for degradation by the ubiquitin–proteasome system. We cloned the novel ubiquitin ligase HRD1, which is involved in ERAD, and showed that HRD1 promoted amyloid precursor protein (APP) ubiquitination and degradation, resulting in decreased generation of amyloid β (Aβ). In addition, suppression of HRD1 expression caused APP accumulation and promoted Aβ generation associated with ER stress and apoptosis. Interestingly, HRD1 levels were significantly decreased in the cerebral cortex of patients with Alzheimer’s disease (AD), and the brains of these patients experienced ER stress. Our recent study revealed that this decrease in HRD1 was due to its insolubilization; however, controversy persists about whether the decrease in HRD1 protein promotes Aβ generation or whether Aβ neurotoxicity causes the decrease in HRD1 protein levels. Here, we review current findings on the mechanism of HRD1 protein loss in the AD brain and the involvement of HRD1 in the pathogenesis of AD. Furthermore, we propose that HRD1 may be a target for novel AD therapeutics. Keywords:: Alzheimer’s disease, amyloid β, endoplasmic reticulum–associated degradation, HRD1, neurodegenerative diseasehttp://www.sciencedirect.com/science/article/pii/S1347861319305572 |
| spellingShingle | Masayuki Kaneko Yasunobu Okuma Yasuyuki Nomura 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 Journal of Pharmacological Sciences |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | http://www.sciencedirect.com/science/article/pii/S1347861319305572 |
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