2006 Fiscal Year Final Research Report Summary
Analysis of the role of Herp in the generation of amyloid β protein and in the ER stress
| Project/Area Number |
16390029
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | National Institute for Longevity Sciences |
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Principal Investigator |
KOMANO Hiroto National Institute for Longevity Sciences, Department of Alzheimer's Disease Research, Section Head, (研究所)・アルツハイマー病研究部, 室長 (40170378)
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| Project Period (FY) |
2004 – 2006
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| Keywords | ER stress / Amyloid β protein / Presenilin / Homocystein / Alzheimer's disease |
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| Research Abstract |
Herp is an endoplasmic reticulum (ER)-stress-inducible membrane protein that has a ubiquitin-like domain (ULD). However, its biological function is not yet known. Previously, we reported that a high expression level of Herp in cells enhances the generation of amyloid β-protein (Aβ) and that Herp interacts with presenilin (PS). Aβ is generated from amyloid precursor protein (APP) by sequential proteolytic cleavages catalyzed by β- and γ-secretases. PS is processed to its stable form by endoproteolysis. The cellular level of processed PS is highly regulated, and excess unprocessed PS enters the ubiquitin/proteasome degradation pathway. Processed PS resides in a high-molecular-weight complex that includes three membrane proteins, namely, Nacastrin (NCT), APH-1 and PEN-2. Accumulating evidence shows that the PS complex is responsible for y-secretase activity. In this study, we addressed the role of Herp in the regulation of PS complex formation. We found that the expression of ULD-deleted Herp markedly inhibited the degradation of unprocessed PS or NCT that fails to be incorporated into the PS complex. We also found that the expression of ULD-deleted Herp decreased a degree of ubiqutination of PS and NCT, while the expression of wild-type Herp enhanced it, strongly suggesting that ULD of Herp is involved for the ubiquitination of PS and NCT. Thus, Herp is likely to play a role, through its ubiquitin-like domain, in the elimination of excess PS or PS cofactors which fail to reside in the PS complex, thereby regulating the intracellular level of the PS complex.
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Research Products
(7 results)
