title: Presenilin-null cells have altered two-pore calcium channel expression and lysosomal calcium: implications for lysosomal function.
abstract: Presenilins are necessary for calcium homeostasis and also for efficient proteolysis through the autophagy/lysosome system. Presenilin regulates both endoplasmic reticulum calcium stores and autophagic proteolysis in a γ-secretase independent fashion. The endo-lysosome system can also act as a calcium store, with calcium efflux channels being recently identified as two-pore channels 1 and 2. Here we investigated lysosomal calcium content and the channels that mediate calcium release from these acidic stores in presenilin knockout cells. We report that presenilin loss leads to a lower total lysosomal calcium store despite the buildup of lysosomes found in these cells. Additionally, we find alterations in two-pore calcium channel protein expression, with loss of presenilin preventing the formation of a high molecular weight species of TPC1 and TPC2. Finally, we find that treatments that disturb lysosomal calcium release lead to a reduction in autophagy function yet lysosomal inhibitors do not alter two-pore calcium channel expression. These data indicate that alterations in lysosomal calcium in the absence of presenilins might be leading to disruptions in autophagy.
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, 3208 Biological Sciences III, Irvine, CA 92697-4545, United States.
authors.forename: Kara M
authors.initials: KM
authors.lastname: Neely Kayala
authors.forename: George D
authors.initials: GD
authors.lastname: Dickinson
authors.forename: Anet
authors.initials: A
authors.lastname: Minassian
authors.forename: Ken C
authors.initials: KC
authors.lastname: Walls
authors.forename: Kim N
authors.initials: KN
authors.lastname: Green
authors.forename: Frank M
authors.initials: FM
authors.lastname: Laferla
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D053766:Presenilin-2 / Q000235:genetics / Q000378:metabolism*; D000097903:Two-Pore Channels
chemical_list: D002118:Calcium; D015220:Calcium Channels; D049452:Green Fluorescent Proteins; D053764:Presenilin-1; D053766:Presenilin-2; C095101:Psen2 protein, mouse; C546784:TPCN1 protein, mouse; D000097903:Two-Pore Channels; C546785:TPCN2 protein, mouse; C580804:presenilin 1, mouse