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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.<\/jats:p>","DOI":"10.1242\/dmm.036590","type":"journal-article","created":{"date-parts":[[2019,4,29]],"date-time":"2019-04-29T13:56:01Z","timestamp":1556546161000},"source":"Crossref","is-referenced-by-count":30,"title":["Inhibition of IGF-1-PI3K-Akt-mTORC2 in lipid rafts increases neuronal vulnerability in a genetic lysosomal glycosphingolipidosis"],"prefix":"10.1242","author":[{"given":"Tuba","family":"Sural-Fehr","sequence":"first","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harinder","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovico","family":"Cantuti-Catelvetri","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongling","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Marshall","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rima","family":"Rebiai","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin J.","family":"Jastrzebski","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria I.","family":"Givogri","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark M.","family":"Rasenick","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1664-6634","authenticated-orcid":false,"given":"Ernesto R.","family":"Bongarzone","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2019,1,1]]},"reference":[{"key":"2019052306535868000_12.5.dmm036590.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-30808-9"},{"key":"2019052306535868000_12.5.dmm036590.2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-0288"},{"key":"2019052306535868000_12.5.dmm036590.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2006.12.003"},{"key":"2019052306535868000_12.5.dmm036590.4","doi-asserted-by":"publisher","DOI":"10.5414\/CPP47034"},{"key":"2019052306535868000_12.5.dmm036590.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2012.01.013"},{"key":"2019052306535868000_12.5.dmm036590.6","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0217-13.2013"},{"key":"2019052306535868000_12.5.dmm036590.7","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2431-14.2015"},{"key":"2019052306535868000_12.5.dmm036590.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.plipres.2015.12.004"},{"key":"2019052306535868000_12.5.dmm036590.9","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-011-0814-2"},{"key":"2019052306535868000_12.5.dmm036590.10","doi-asserted-by":"crossref","unstructured":"Cole, R. and de Vellis, J. 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