Abstract：
: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.
journal_name
Celljournal_title
Cellauthors
Lee JH,Yu WH,Kumar A,Lee S,Mohan PS,Peterhoff CM,Wolfe DM,Martinez-Vicente M,Massey AC,Sovak G,Uchiyama Y,Westaway D,Cuervo AM,Nixon RAdoi
10.1016/j.cell.2010.05.008subject
Has Abstractpub_date
2010-06-25 00:00:00pages
1146-58issue
7eissn
0092-8674issn
1097-4172pii
S0092-8674(10)00544-1journal_volume
141pub_type
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