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


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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    • "Mutations in PS1, a multi-spanning transmembranal aspartic protease which possesses the proteolytic activity of the c-secretase complex (De Strooper et al, 1998), are accountable for the majority of familial AD cases (Bertram & Tanzi, 2008). PS1 was shown to play crucial roles in key biological functions including autophagy (Lee et al, 2010), the mediation of correct interactions between the ER and mitochondria (Area-Gomez et al, 2009), as well as in the maintenance of calcium homeostasis (Bezprozvanny & Mattson, 2008). Although rare, mutation-linked neurodegeneration cases provide invaluable hints that can help decipher the mechanisms that underlie the development of these maladies. "
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    ABSTRACT: Do different neurodegenerative maladies emanate from the failure of a mutual protein folding mechanism? We have addressed this question by comparing mutational patterns that are linked to the manifestation of distinct neurodegenerative disorders and identified similar neurodegeneration-linked proline substitutions in the prion protein and in presenilin 1 that underlie the development of a prion disorder and of familial Alzheimer's disease (fAD), respectively. These substitutions were found to prevent the endoplasmic reticulum (ER)-resident chaperone, cyclophilin B, from assisting presenilin 1 to fold properly, leading to its aggregation, deposition in the ER, reduction of c-secretase activity, and impaired mito-chondrial distribution and function. Similarly, reduced quantities of the processed, active presenilin 1 were observed in brains of cyclophilin B knockout mice. These discoveries imply that reduced cyclophilin activity contributes to the development of distinct neurodegenerative disorders, propose a novel mechanism for the development of certain fAD cases, and support the emerging theme that this disorder can stem from aberrant presenilin 1 function. This study also points at ER chaperones as targets for the development of counter-neurodegeneration therapies.
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    • "Presenilin 1 plays an important role in Ca 2+ homeostasis and autophagy/lysosomal protein degradation, beyond its wellstudied catalytic role as part of g-secretase (Lee et al., 2010; Tu et al., 2006). However, the relationship between two major g-secretase independent functions of PS1, namely maintenance of Ca 2+ homeostasis and lysosomal proteolysis, is poorly understood. "
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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.
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