Abstract
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.
Highlights
Mutations in SPG11, leading to loss of spatacsin function, impair the formation of membrane tubules in lysosomes and cause lysosomal lipid accumulation
We demonstrate that the resulting modification in cytosolic calcium levels contributes to the impairment of lysosome tubulation and accumulation of cholesterol in late endosomes/lysosomes and that this process is TFEB-dependent
Since mutations in SPG11 cause neurodegeneration[3], we evaluated the impact of loss of spatacsin function on cholesterol distribution in neuronal models
Summary
Mutations in SPG11, leading to loss of spatacsin function, impair the formation of membrane tubules in lysosomes and cause lysosomal lipid accumulation. We show that the loss of spatacsin function and the associated inhibition of tubule formation in late endosomes/ lysosomes leads to the accumulation of cholesterol in this compartment, due to its impaired export out of the organelle. This results in a decrease in the level of plasma membrane cholesterol that disturbs intracellular calcium homeostasis. We demonstrate that the resulting modification in cytosolic calcium levels contributes to the impairment of lysosome tubulation and accumulation of cholesterol in late endosomes/lysosomes and that this process is TFEB-dependent
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