Lysosomal Proteolysis and Autophagy Require Presenilin 1 and Are Disrupted by Alzheimer-Related PS1 Mutations

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...

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Published in:Cell 2010-06, Vol.141 (7), p.1146-1158
Main Authors: Lee, Ju-Hyun, Yu, W. Haung, Kumar, Asok, Lee, Sooyeon, Mohan, Panaiyur S., Peterhoff, Corrinne M., Wolfe, Devin M., Martinez-Vicente, Marta, Massey, Ashish C., Sovak, Guy, Uchiyama, Yasuo, Westaway, David, Cuervo, Ana Maria, Nixon, Ralph A.
Format: Article
Language:English
Subjects:
Alzheimer Disease - metabolism
Alzheimer Disease - pathology
Animals
Autophagy
Blastocyst - metabolism
Cell Line
CELLBIO
Gene Deletion
Gene Knockout Techniques
Glycosylation
Humans
HUMDISEASE
Hydrolysis
Lysosomes - metabolism
Mice
Mice, Knockout
Neurons - metabolism
Presenilin-1 - genetics
Presenilin-1 - metabolism
Proteins - metabolism
Vacuolar Proton-Translocating ATPases - metabolism
Vacuoles - metabolism
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Summary: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. [Display omitted] [Display omitted] ► Presenilin-1 (PS1) is essential for lysosomal acidification and protein degradation ► v-ATPase V0a1 subunit glycosylation and delivery to lysosomes requires PS1 ► PS1 mutations impair lysosomal acidification and protein turnover by autophagy ► Neurons in PS1-deficient mice have lysosomal acidification deficits
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2010.05.008