title: Presenilin 1 Maintains Lysosomal Ca(2+) Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification.
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.
authors: Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA; Department of Psychiatry, New York University, New York, NY 10016, USA.
authors: Ju-Hyun
authors: JH
authors: Lee
authors: Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA.
authors: Mary Kate
authors: MK
authors: McBrayer
authors: Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA.
authors: Devin M
authors: DM
authors: Wolfe
authors: Division of Pathophysiology and Repair, Cardiff University, Cardiff CF10 3XQ, UK.
authors: Luke J
authors: LJ
authors: Haslett
authors: Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA; Department of Pathology, New York University, New York, NY 10016, USA.
authors: Asok
authors: A
authors: Kumar
authors: Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA.
authors: Yutaka
authors: Y
authors: Sato
authors: Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA.
authors: Pearl P Y
authors: PP
authors: Lie
authors: Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA; Department of Psychiatry, New York University, New York, NY 10016, USA.
authors: Panaiyur
authors: P
authors: Mohan
authors: Department of Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Erin E
authors: EE
authors: Coffey
authors: Pharmaceutical Science and Ophthalmology, University of Colorado, Aurora, CO 80045, USA.
authors: Uday
authors: U
authors: Kompella
authors: Department of Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Claire H
authors: CH
authors: Mitchell
authors: Division of Pathophysiology and Repair, Cardiff University, Cardiff CF10 3XQ, UK.
authors: Emyr
authors: E
authors: Lloyd-Evans
authors: Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA; Department of Psychiatry, New York University, New York, NY 10016, USA; Department of Cell Biology, New York University, New York, NY 10016, USA. Electronic address: nixon@nki.rfmh.org.
authors: Ralph A
authors: RA
authors: Nixon
mesh_terms: D000818:Animals; D001343:Autophagy; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D006706:Homeostasis; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D050051:Transient Receptor Potential Channels / Q000378:metabolism*; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism*
chemical_list: C512321:Mcoln1 protein, mouse; D053764:Presenilin-1; D050051:Transient Receptor Potential Channels; D025262:Vacuolar Proton-Translocating ATPases; D002118:Calcium