Abstract
ABSTRACTGlycosphingolipid (GSL) accumulation is implicated in the neuropathology of several lysosomal conditions, such as Krabbe 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. GSLs 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 disease, we provide a mechanism explaining the inactivation of lipid raft (LR)-associated IGF-1–PI3K–Akt–mTORC2, a pathway of crucial importance for neuronal function and survival. We show that psychosine, the GSL that accumulates in Krabbe 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 LRs. 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 desensitizes 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. This article has an associated First Person interview with the first author of the paper.
Highlights
Glycosphingolipids (GSLs) are key components of neural membranes, and defects in their metabolism have negative consequences on neuronal and glial survival (Ballabio, 2009; Onyenwoke and Brenman, 2015; Settembre et al, 2008; Sural-Fehr and Bongarzone, 2016)
To examine the dynamics of this regulation, we looked at the intracellular levels of phosphorylated Akt ( p-Akt) and p-ERK in conditions where we detected a significant change in cell morphology (Fig. 1A, 30 min)
By studying IGF-1 receptor (IGF-1R) activation, our study demonstrates that psychosine uncouples downstream Akt phosphorylation by interfering with the recruitment of the upstream kinases phosphoinositide 3-kinase (PI3K) and mTOR complex 2 (mTORC2) to lipid raft (LR)
Summary
Glycosphingolipids (GSLs) are key components of neural membranes, and defects in their metabolism have negative consequences on neuronal and glial survival (Ballabio, 2009; Onyenwoke and Brenman, 2015; Settembre et al, 2008; Sural-Fehr and Bongarzone, 2016). Phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3; PIP3] generation by PI3K is the key step in the recruitment of Akt to the plasma membrane, where it is phosphorylated by PDK1 and mTOR complex 2 (mTORC2), resulting in its activation. After release from the membrane, Akt regulates a myriad of downstream targets in the cytoplasm, including GSK3β and mTOR complex 1 (mTORC1) (Romanelli et al, 2009). In this context, we hypothesized that inhibition of the Akt pathway by psychosine involves the disruption of LR integrity and interferes with the proper activation of subsequent signaling within these domains
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