| Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. | |
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MedLine Citation:
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PMID: 20541250 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Macroautophagy is a lysosomal degradative pathway essential for neuron survival. Here, we show that macroautophagy requires the Alzheimer's disease (AD)-related protein presenilin-1 (PS1). In PS1 null blastocysts, neurons from mice hypomorphic for PS1 or conditionally depleted of PS1, substrate proteolysis and autophagosome clearance during macroautophagy are prevented as a result of a selective impairment of autolysosome acidification and cathepsin activation. These deficits are caused by failed PS1-dependent targeting of the v-ATPase V0a1 subunit to lysosomes. N-glycosylation of the V0a1 subunit, essential for its efficient ER-to-lysosome delivery, requires the selective binding of PS1 holoprotein to the unglycosylated subunit and the Sec61alpha/oligosaccharyltransferase complex. PS1 mutations causing early-onset AD produce a similar lysosomal/autophagy phenotype in fibroblasts from AD patients. PS1 is therefore essential for v-ATPase targeting to lysosomes, lysosome acidification, and proteolysis during autophagy. Defective lysosomal proteolysis represents a basis for pathogenic protein accumulations and neuronal cell death in AD and suggests previously unidentified therapeutic targets. |
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Authors:
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Ju-Hyun Lee; W Haung Yu; Asok Kumar; Sooyeon Lee; Panaiyur S Mohan; Corrinne M Peterhoff; Devin M Wolfe; Marta Martinez-Vicente; Ashish C Massey; Guy Sovak; Yasuo Uchiyama; David Westaway; Ana Maria Cuervo; Ralph A Nixon |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-06-10 |
Journal Detail:
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Title: Cell Volume: 141 ISSN: 1097-4172 ISO Abbreviation: Cell Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-07-06 Completed Date: 2010-07-13 Revised Date: 2013-05-13 |
Medline Journal Info:
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Nlm Unique ID: 0413066 Medline TA: Cell Country: United States |
Other Details:
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Languages: eng Pagination: 1146-58 Citation Subset: IM |
Affiliation:
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Center for Dementia Research, Nathan S. Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Alzheimer Disease
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metabolism*,
pathology Animals Autophagy* Blastocyst / metabolism Cell Line Gene Deletion Gene Knockout Techniques Glycosylation Humans Hydrolysis Lysosomes / metabolism* Mice Mice, Knockout Neurons / metabolism Presenilin-1 / genetics*, metabolism* Proteins / metabolism* Vacuolar Proton-Translocating ATPases / metabolism Vacuoles / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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P01 AG017617/AG/NIA NIH HHS; P01AG017617/AG/NIA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Presenilin-1; 0/Proteins; EC 3.6.1.-/Vacuolar Proton-Translocating ATPases |
| Comments/Corrections | |
Comment In:
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Cell. 2010 Jun 25;141(7):1112-4
[PMID:
20602994
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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