Community Research and Development Information Service - CORDIS


ER-HSP Report Summary

Project ID: 311149
Funded under: FP7-IDEAS-ERC
Country: France

Final Report Summary - ER-HSP (Role of endoplasmic reticulum in neurodegeneration: physiopathology of a form of hereditary spastic paraplegia as a model)

The cytoplasm of every cell, including neurons, is separated in various subcellular organelles, allowing compartmentalization of biochemical functions. However, it is not known how the functions of the different organelles are linked. Furthermore, it has never been investigated how they can contribute to neuronal death. We used as a model hereditary spastic paraplegias (HSP), a group of motor neuron diseases that are caused by mutations in genes leading to alteration of subcellular compartments, such as changes in the morphology of endoplasmic reticulum or lysosome dysfunction. We focused on models of the pathology due to mutations in the gene SPG11 to investigate the mechanisms linking endoplasmic reticulum or lysosome dysfunction to neurodegeneration. We demonstrate that loss of spatacsin, caused by mutations in the gene SPG11, leads to accumulation of lipids in lysosomes. We identified two classes of lipids that accumulate in lysosomes in models of the SPG11 pathology: cholesterol and gangliosides. We showed that alteration of cholesterol levels in lysosomes led to secondary alteration of endoplasmic reticulum morphology and dynamics, linking the role of the two subcellular compartments in the physiopathology of SPG11. Furthermore, we demonstrated that accumulation of gangliosides in lysosomes contributed to neurodegeneration in models of SPG11, and therefore we identified a putative therapeutic target for this severe condition.

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