ArticleDisease models & mechanisms2019
Inhibition of the IGF-1-PI3K-Akt-mTORC2 pathway in lipid rafts increases neuronal vulnerability in a genetic lysosomal glycosphingolipidosis.
Article in Disease models & mechanisms, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 36 citations in OpenAlex.
- The Follicular Immune Checkpoint: PD-1/PD-L1 and Immune Tolerance in Oocyte Competence and IVF Failure.International journal of molecular sciences · 2026Review
- Elucidating the vasoprotective mechanism of Tetrahydrocurcumin: from unbiased transcriptomic discovery to targeted validation of the PI3K/AKT pathway.BMC complementary medicine and therapies · 2026Article
- mTOR in radiotherapy of lung cancer: Mechanisms of radiation resistance and therapeutic implications (Review).International journal of oncology · 2026Review
- Impaired docking and recycling of synaptic vesicles in inherited lysosomal sphingolipidoses.Cell communication and signaling : CCS · 2025Article
- A scoping review of stem cell models of leukodystrophies: advances in understanding pathophysiological mechanisms.NPJ genomic medicine · 2025Article
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- Deficiency of galactosyl-ceramidase in adult oligodendrocytes worsens disease severity during chronic experimental allergic encephalomyelitis.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Is cholesterol both the lock and key to abnormal transmembrane signals in Autism Spectrum Disorder?Lipids in health and disease · 2024Article
- Exploring Pro-Inflammatory Immunological Mediators: Unraveling the Mechanisms of Neuroinflammation in Lysosomal Storage Diseases.Biomedicines · 2023Review
- Preclinical studies in Krabbe disease: A model for the investigation of novel combination therapies for lysosomal storage diseases.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Review
- Malignant Brain Aging: The Formidable Link Between Dysregulated Signaling Through Mechanistic Target of Rapamycin Pathways and Alzheimer's Disease (Type 3 Diabetes).Journal of Alzheimer's disease : JAD · 2023Review
- Extracellular vesicles carrying HIV-1 Nef induce long-term hyperreactivity of myeloid cells.Cell reports · 2022Article
- Review
- Crosstalk between Lipid Rafts and Aging: New Frontiers for Delaying Aging.Aging and disease · 2022Article
- CRISPR-Cas9 Knock-In of T513M and G41S Mutations in the Murine β-Galactosyl-Ceramidase Gene Re-capitulates Early-Onset and Adult-Onset Forms of Krabbe Disease.Frontiers in molecular neuroscience · 2022Article
- Krabbe disease: New hope for an old disease.Neuroscience letters · 2021Review
- How Lysosomes Sense, Integrate, and Cope with Stress.Trends in biochemical sciences · 2021Review
- Krabbe Disease: Prospects of Finding a Cure Using AAV Gene Therapy.Frontiers in medicine · 2021Review
- Synaptic Function and Dysfunction in Lysosomal Storage Diseases.Frontiers in cellular neuroscience · 2021Article
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
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. This article has an associated First Person interview with the first author of the paper.
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