Document Detail

Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations.
MedLine Citation:
PMID:  20541250     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-06-10
Journal Detail:
Title:  Cell     Volume:  141     ISSN:  1097-4172     ISO Abbreviation:  Cell     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-07-06     Completed Date:  2010-07-13     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  0413066     Medline TA:  Cell     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1146-58     Citation Subset:  IM    
Center for Dementia Research, Nathan S. Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA.
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MeSH Terms
Alzheimer Disease / metabolism*,  pathology
Blastocyst / metabolism
Cell Line
Gene Deletion
Gene Knockout Techniques
Lysosomes / metabolism*
Mice, Knockout
Neurons / metabolism
Presenilin-1 / genetics*,  metabolism*
Proteins / metabolism*
Vacuolar Proton-Translocating ATPases / metabolism
Vacuoles / metabolism
Grant Support
Reg. No./Substance:
0/Presenilin-1; 0/Proteins; EC 3.6.1.-/Vacuolar Proton-Translocating ATPases
Comment In:
Cell. 2010 Jun 25;141(7):1112-4   [PMID:  20602994 ]

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