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

Cell. 2010 Jun 25;141(7):1146-58. doi: 10.1016/j.cell.2010.05.008. Epub 2010 Jun 10.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Animals
  • Autophagy*
  • Blastocyst / metabolism
  • Cell Line
  • Gene Deletion
  • Gene Knockout Techniques
  • Glycosylation
  • Humans
  • Hydrolysis
  • Lysosomes / metabolism*
  • Mice
  • Mice, Knockout
  • Neurons / metabolism
  • Presenilin-1 / genetics*
  • Presenilin-1 / metabolism*
  • Proteins / metabolism*
  • Vacuolar Proton-Translocating ATPases / metabolism
  • Vacuoles / metabolism

Substances

  • Presenilin-1
  • Proteins
  • Vacuolar Proton-Translocating ATPases