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

By Ju-Hyun Lee, W. H. Yu, Asok Kumar, Sooyeon Lee, P. Mohan, Corrinne M. Peterhoff, Devin M. Wolfe, Marta Martínez-Vicente, Ashish C. Massey, G. Sovak and 4 more. Cell, 2010

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SUMMARY 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 due to a selective impairment of autolysosome acidification and cathepsin activation. These deficits are caused by failed PS1-dependent targeting of the v-ATPase 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 novel therapeutic targets.

Subfields: Cell Biology, Epidemiology, Physiology

View Paper: https://www.semanticscholar.org/paper/7a58e3a2b70594d0051cc55102d2e16509560f54

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Citations in the corpus

Lysosomes as a therapeutic target (2019, result): “These findings strongly support the hypothesis that dysfunction of endo/lysosomal pathways is pivotal in AD.”
The cell biology of disease: lysosomal storage disorders: the cellular impact of lysosomal dysfunction. (2012, neutral): “Furthermore, the morphology of the Golgi apparatus was altered in form of Alzheimer’s disease, is known to impair lysosomal clearance of autophagosomes (Esselens et al., 2004; Wilson et al., 2004; J.H. Lee et al., 2010).”
Autophagy: Renovation of Cells and Tissues (2011, background): “Indeed, accumulation of autophagic vacuoles has been demonstrated in human neurodegenerative diseases (Lee et al., 2010; Nixon et al., 2008).”
Mitophagy and Alzheimer’s disease: cellular and molecular mechanisms (2017, background): “Mutations in PS1 can impair autophagy/mitophagy [70].”
Recent advances in Alzheimer’s disease: mechanisms, clinical trials and new drug development strategies (2024, background): “266 However, there are inconsistent views on a series of events caused by defects in PS1, including impaired maturation of V0a1 in lysosomes, V-ATPase dysfunction, and lysosomal acidi ﬁ cation defects.”
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (2012, neutral): “, mRFP/ mCherry-GFP-LC3 probes [see Tandem mRFP/mCherry-GFP fluorescence microscopy], or Bodipy-pepstatin A detection of CTSD in an activated form within an acidic compartment), and, when appropriate, by excluding markers of other vesicular components.(57,61,62)”
Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities. (2017, positive): “Familial AD associated mutations in PS-1 result in decreased maturation of the lysosomal v-ATPase and thus increased lysosomal pH (Coffey et al., 2014; Lee et al., 2010; Wolfe et al., 2013), which would be predicted to reduce autophagosome clearance.”
Autophagy Failure in Alzheimer's Disease – Locating the Primary Defect (2011, background): “PS1 deficiency is associated with the failure of the V0a1 subunit of v-ATPase to become N-glycosylated in the ER, rendering it susceptible to increased degradation before it can be delivered to autolysosomes/lysosomes at levels sufficient to support normal lysosomal acidification (Lee et al., 2010).”
Neuronal Cell Death. (2018, positive): “A causal link between the absence of PSEN1 activity, lysosomal acidification, and reduced lysosomal calcium release is supported by the finding that delivery of acidic poly (lactic-coglycolic) acid (PLGA) nanoparticles to PSEN1 knockout blastocysts or PSEN1 knockdown cells mediated by siRNA reacidif”