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.

中文翻译：

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抑制脂筏中的 IGF-1-PI3K-Akt-mTORC2 通路会增加遗传性溶酶体鞘糖脂沉积症中神经元的脆弱性。


鞘糖脂 (GSL) 积累与多种溶酶体疾病（例如克拉伯病）的神经病理学有关，也可能导致成人发病的疾病（例如帕金森病、阿尔茨海默病和多发性硬化症）中的神经元和神经胶质功能障碍。 GSL 在细胞膜中积聚并破坏其结构；然而，膜破坏如何导致细胞功能障碍仍然未知。使用克拉伯病的真实细胞和动物模型，我们提供了一种解释脂筏 (LR) 相关 IGF-1-PI3K-Akt-mTORC2 失活的机制，这是一种对神经元功能和存活至关重要的途径。我们发现，在 Krabbe 病中积聚的精神碱 (GSL) 通过解偶联 IGF-1 受体磷酸化与下游 Akt 激活，导致剂量依赖性 LR 介导的对该途径的抑制。这是通过干扰 PI3K 和 mTORC2 向 LR 的募集而发生的。 Akt 抑制可以通过持续的 IGF-1 刺激来逆转，但仅限于精神嘧啶累积达到阈值水平之前的时间窗口内。我们的研究表明细胞表面 mTORC2 活性的 LR 依赖性调节与遗传性神经退行性疾病之间存在先前未知的联系。我们的结果表明，精神嘧啶对 LR 的破坏通过抑制从质膜到细胞内区室的信号传递而使细胞对细胞外生长因子不敏感。这种机制还可以作为一种机制模型，用于了解脂质逐渐积累导致的膜结构改变如何破坏细胞功能，并对其他遗传性鞘脂沉积症和成人神经退行性疾病具有潜在影响。 本文有对该论文第一作者的相关第一人称采访。