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

Center for Dementia Research, Nathan S. Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA.
Cell (Impact Factor: 32.24). 06/2010; 141(7):1146-58. DOI: 10.1016/j.cell.2010.05.008
Source: PubMed

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.

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Available from: Sooyeon Lee, Sep 28, 2015
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    • "Procedures were performed as previously described (Lee et al., 2010). "
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    ABSTRACT: Presenilin 1 (PS1) deletion or Alzheimer's disease (AD)-linked mutations disrupt lysosomal acidification and proteolysis, which inhibits autophagy. Here, we establish that this phenotype stems from impaired glycosylation and instability of vATPase V0a1 subunit, causing deficient lysosomal vATPase assembly and function. We further demonstrate that elevated lysosomal pH in Presenilin 1 knockout (PS1KO) cells induces abnormal Ca(2+) efflux from lysosomes mediated by TRPML1 and elevates cytosolic Ca(2+). In WT cells, blocking vATPase activity or knockdown of either PS1 or the V0a1 subunit of vATPase reproduces all of these abnormalities. Normalizing lysosomal pH in PS1KO cells using acidic nanoparticles restores normal lysosomal proteolysis, autophagy, and Ca(2+) homeostasis, but correcting lysosomal Ca(2+) deficits alone neither re-acidifies lysosomes nor reverses proteolytic and autophagic deficits. Our results indicate that vATPase deficiency in PS1 loss-of-function states causes lysosomal/autophagy deficits and contributes to abnormal cellular Ca(2+) homeostasis, thus linking two AD-related pathogenic processes through a common molecular mechanism. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 08/2015; 12(9). DOI:10.1016/j.celrep.2015.07.050 · 8.36 Impact Factor
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    • "It has recently emerged that Auguste D. had a point mutation in presenilin 1 (PS1) [59], a subunit of gsecretase , which regulates the intramembrane cleavage of APP and production of Ab. While EOADcausing mutations in PS1 and PS2 are best known for instigating early amyloid plaque deposition in the brain, loss of PS1 function has also been found to reduce lysosomal Ca 2þ stores and increase lysosomal pH, which causes primary and secondary storage phenotypes [60] [61]. In Down's Syndrome, triplication of the APP gene has been found to alter endosomal function [62] and impair lysosomal flux due to hyperactivated PI3 kinase/Akt/mTOR signalling [63]. "
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    ABSTRACT: For over a century, researchers have observed similar neurodegenerative hallmarks in brains of people affected by rare early-onset lysosomal storage diseases and late-onset neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Increasing evidence suggests these apparently disparate diseases share a common underlying feature, namely, a dysfunctional clearance of cellular cargo through the secretory-endosomal-autophagic-lysosomal-exocytic (SEALE) network. By providing examples of rare and common neurodegenerative diseases known to have pathologically altered cargo flux through the SEALE network, we explore the unifying hypothesis that impaired catabolism or exocytosis of SEALE cargo, places a burden of stress on neurons that initiates pathogenesis. We also describe how a growing understanding of genetic, epigenetic and age-related modifications of the SEALE network, has inspired a number of novel disease-modifying therapeutic approaches aimed at alleviating SEALE storage and providing therapeutic benefit to people affected by these devastating diseases across the age spectrum. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Best Practice & Research: Clinical Endocrinology & Metabolism 09/2014; 29(2). DOI:10.1016/j.beem.2014.08.009 · 4.60 Impact Factor
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    • "A recent study reported that aberrant lysosomal function can elicit innate immune responses (Hasan et al., 2013). In various tissues, the downstream consequences of lysosomal dysfunction usually include inflammation, resulting in pathogenesis (Lee et al., 2010). It is likely that disturbances in the homeostasis of RPE cells, due to accumulation of undegraded intracellular material in the cKO mice, trigger a parainflammatory response in an attempt to restore normal RPE function. "
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    ABSTRACT: Although chronic inflammation is believed to contribute to the pathology of age-related macular degeneration (AMD), knowledge regarding the events that elicit the change from para-inflammation to chronic inflammation in the pathogenesis of AMD is lacking. We propose here that lipocalin-2 (LCN2), a mammalian innate immunity protein that is trafficked to the lysosomes, may contribute to this process. It accumulates significantly with age in retinal pigment epithelial (RPE) cells of Cryba1 conditional knockout (cKO) mice, but not in control mice. We have recently shown that these mice, which lack βA3/A1-crystallin specifically in RPE, have defective lysosomal clearance. The age-related increase in LCN2 in the cKO mice is accompanied by increases in chemokine (C-C motif) ligand 2 (CCL2), reactive gliosis, and immune cell infiltration. LCN2 may contribute to induction of a chronic inflammatory response in this mouse model with AMD-like pathology.
    Aging cell 09/2014; 13(6). DOI:10.1111/acel.12274 · 6.34 Impact Factor
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