title: Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations.
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.
authors.affiliation: Center for Dementia Research, Nathan S. Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA.
authors.forename: Ju-Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: W Haung
authors.initials: WH
authors.lastname: Yu
authors.forename: Asok
authors.initials: A
authors.lastname: Kumar
authors.forename: Sooyeon
authors.initials: S
authors.lastname: Lee
authors.forename: Panaiyur S
authors.initials: PS
authors.lastname: Mohan
authors.forename: Corrinne M
authors.initials: CM
authors.lastname: Peterhoff
authors.forename: Devin M
authors.initials: DM
authors.lastname: Wolfe
authors.forename: Marta
authors.initials: M
authors.lastname: Martinez-Vicente
authors.forename: Ashish C
authors.initials: AC
authors.lastname: Massey
authors.forename: Guy
authors.initials: G
authors.lastname: Sovak
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.forename: David
authors.initials: D
authors.lastname: Westaway
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Cuervo
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Nixon
mesh_terms: 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
chemical_list: D053764:Presenilin-1; D011506:Proteins; D025262:Vacuolar Proton-Translocating ATPases