Presenilin-null cells have altered two-pore calcium channel expression and lysosomal calcium: implications for lysosomal function

Brain Res. 2012 Dec 13;1489:8-16. doi: 10.1016/j.brainres.2012.10.036. Epub 2012 Oct 24.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autophagy / physiology*
  • Calcium / metabolism
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Cells, Cultured
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Expression / physiology
  • Green Fluorescent Proteins / genetics
  • Lysosomes / metabolism*
  • Mice
  • Mice, Knockout
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism*
  • Presenilin-2 / genetics
  • Presenilin-2 / metabolism*

Substances

  • Calcium Channels
  • Presenilin-1
  • Presenilin-2
  • Psen2 protein, mouse
  • TPCN1 protein, mouse
  • TPCN2 protein, mouse
  • presenilin 1, mouse
  • Green Fluorescent Proteins
  • Calcium