Inhibition of IGF-1-PI3K-Akt-mTORC2 in lipid rafts increases neuronal vulnerability in a genetic lysosomal glycosphingolipidosis.

Glycosphingolipid (GSL) accumulation is implicated in the neuropathology of several lysosomal conditions such as Krabbe's Disease, and may also contribute to neuronal and glial dysfunction in adult onset conditions such as Parkinson's disease, Alzheimer's disease and Multiple Sclerosis. GSL accumulate in cellular membranes and disrupt their structure, however how membrane disruption leads to cellular dysfunction remains unknown. Using authentic cellular and animal models for Krabbe's disease, we provide a mechanism explaining the inactivation of lipid raft (LR)-associated IGF-1-PI3K-mTORC2, a pathway of crucial importance for neuronal function and survival. We show that psychosine, the GSL accumulated in Krabbe's disease, leads to a dose-dependent LR-mediated inhibition of this pathway by uncoupling IGF-1 receptor phosphorylation from downstream Akt activation. This occurs by interfering with the recruitment of PI3K and mTORC2 to LR. Akt inhibition can be reversed by sustained IGF-1 stimulation, but only during a time window before psychosine accumulation reaches a threshold level. Our study shows a previously unknown connection between LR-dependent regulation of mTORC2 activity at the cell surface and a genetic neurodegenerative disease. Our results show that LR disruption by psychosine de-sensitizes cells to extracellular growth factors by inhibiting signal transmission from the plasma membrane to intracellular compartments. This mechanism serves also as a mechanistic model to understand how alterations of the membrane architecture by the progressive accumulation of lipids undermines cell function, with potential implications in other genetic sphingolipidoses and adult neurodegenerative conditions.