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 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.
Lee
Ju-Hyun
JH
Center for Dementia Research, Nathan S. Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA.
Yu
W Haung
WH
Kumar
Asok
A
Lee
Sooyeon
S
Mohan
Panaiyur S
PS
Peterhoff
Corrinne M
CM
Wolfe
Devin M
DM
Martinez-Vicente
Marta
M
Massey
Ashish C
AC
Sovak
Guy
G
Uchiyama
Yasuo
Y
Westaway
David
D
Cuervo
Ana Maria
AM
Nixon
Ralph A
RA
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001343:Autophagy; D001755:Blastocyst / Q000378:metabolism; D002460:Cell Line; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D006031:Glycosylation; D006801:Humans; D006868:Hydrolysis; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism; D014617:Vacuoles / Q000378:metabolism
D053764:Presenilin-1; D011506:Proteins; D025262:Vacuolar Proton-Translocating ATPases