Loss of spatacsin impairs cholesterol trafficking and calcium homeostasis

Commun Biol. 2019 Oct 17:2:380. doi: 10.1038/s42003-019-0615-z. eCollection 2019.


Mutations in SPG11, leading to loss of spatacsin function, impair the formation of membrane tubules in lysosomes and cause lysosomal lipid accumulation. However, the full nature of lipids accumulating in lysosomes and the physiological consequences of such accumulation are unknown. Here we show that loss of spatacsin inhibits the formation of tubules on lysosomes and prevents the clearance of cholesterol from this subcellular compartment. Accumulation of cholesterol in lysosomes decreases cholesterol levels in the plasma membrane, enhancing the entry of extracellular calcium by store-operated calcium entry and increasing resting cytosolic calcium levels. Higher cytosolic calcium levels promote the nuclear translocation of the master regulator of lysosomes TFEB, preventing the formation of tubules and the clearance of cholesterol from lysosomes. Our work reveals a homeostatic balance between cholesterol trafficking and cytosolic calcium levels and shows that loss of spatacsin impairs this homeostatic equilibrium.

Keywords: Lysosomes; Mechanisms of disease; Sterols.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Calcium / metabolism*
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Cholesterol / metabolism*
  • Cytosol / metabolism
  • Female
  • Fibroblasts / metabolism
  • Homeostasis
  • Humans
  • Lysosomes / metabolism
  • Lysosomes / ultrastructure
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proteins / genetics*
  • Proteins / metabolism*


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Proteins
  • SPG11 protein, human
  • SPG11 protein, mouse
  • Tcfeb protein, mouse
  • Cholesterol
  • Calcium