Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations

Ju Hyun Lee, W. Haung Yu, Asok Kumar, Sooyeon Lee, Panaiyur S. Mohan, Corrinne M. Peterhoff, Devin M. Wolfe, Marta Martinez-Vicente, Ashish C. Massey, Guy Sovak, Yasuo Uchiyama, David Westaway, Ana Maria Cuervo, Ralph A. Nixon

Research output: Contribution to journalArticle

627 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1146-1158
Number of pages13
JournalCell
Volume141
Issue number7
DOIs
StatePublished - Jun 2010

Fingerprint

Proteolysis
Presenilin-1
Autophagy
Mutation
Lysosomes
Alzheimer Disease
Acidification
Neurons
Adenosine Triphosphatases
Glycosylation
Cathepsins
Blastocyst
Cell death
Fibroblasts
Proteins
Cell Death
Chemical activation
Phenotype
Substrates

Keywords

  • Cellbio
  • Humdisease

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Lee, J. H., Yu, W. H., Kumar, A., Lee, S., Mohan, P. S., Peterhoff, C. M., ... Nixon, R. A. (2010). Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell, 141(7), 1146-1158. https://doi.org/10.1016/j.cell.2010.05.008

Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. / 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.

In: Cell, Vol. 141, No. 7, 06.2010, p. 1146-1158.

Research output: Contribution to journalArticle

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, RA 2010, 'Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations', Cell, vol. 141, no. 7, pp. 1146-1158. https://doi.org/10.1016/j.cell.2010.05.008
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. / Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. In: Cell. 2010 ; Vol. 141, No. 7. pp. 1146-1158.
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