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

Abstract

Glycosphingolipid (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.

Krabbe disease successfully treated via monotherapy of intrathecal gene therapy

“…Ongoing studies using MALDI mass spectrometry will help elucidate the temporospatial accumulation of psychosine in canine GLD. It has recently been shown in the twitcher mouse that inhibitory effects of psychosine are visible as early as embryonic day 12 (33). Taken together, these findings reiterate the importance of early intervention.…”

Synaptic Function and Dysfunction in Lysosomal Storage Diseases

“…In sphingolipidoses such as KD and MLD, lysosomal defects lead to the progressive accumulation of undegraded sphingolipids in multiple membrane compartments. The build-up of psychosine (KD) and sulfatides (MLD) in lipid rafts of brain membranes provided an initial rationale to understand the link between membrane deformation and synaptic dysfunction in these LSDs (White et al, 2009 ; Moyano et al, 2014 ; Sural-Fehr et al, 2019 ). Psychosine is the main undegraded sphingolipid accumulated in KD caused by the deficiency of galactosylceramidase ( Table 1 ; White et al, 2009 ).…”

Neuronal Signaling Involved in Neuronal Polarization and Growth: Lipid Rafts and Phosphorylation

“…TrkB (Assaife-Lopes et al, 2010;Mandyam et al, 2017) IGF-1R (Sural-Fehr et al, 2019) Neuropilin/Plexin complex (Dang et al, 2012) Integrin (Decker et al, 2004) Thy-1 (Ledesma et al, 1998) B. Protein kinases CaMKI (Davare et al, 2009) Glycogen synthase kinase-3 (Sui et al, 2006) SAD-B (Rodríguez-Asiain et al, 2011) Akt (Bryant et al, 2009) Fyn (Ko et al, 2005) C. Other intracellular signaling molecules PI3K (Zheng et al, 2014) Wnt-Dvl (Frizzled; Haack et al, 2015) Ras/Rap (Zhang et al, 2018) Rac1 (Fujitani et al, 2005;Grider et al, 2009;Köster et al, 2014;Lee et al, 2016) V-ATPase (Kanda et al, 2013;Makdissy et al, 2018) The proteins involved in polarization are listed above.…”