Lysoglycosphingolipids have the ability to induce cell death through direct PI3K inhibition

We propose lysoglycosphingolipids (lysoGSLs) as a cause of neuronal cell death in sphingolipidoses. In sphingolipidoses, glycosphingolipids accumulate excessively in lysosomes and lysoGSLs are generated. These lysoGSLs directly inhibit phosphoinositide 3-kinase (PI3K), suppress downstream PI3K/Akt signaling, and induce apoptotic signaling. Since multiple lysoGSLs cause PI3K inhibition, lysoGSLs are thought to be a common cause of neuronal cell death in sphingolipidoses. This finding suggests a new therapeutic approach to sphingolipidoses, which are extremely difficult to treat. AbstractSphingolipidoses are inherited metabolic disorders associated with glycosphingolipids accumulation, neurodegeneration, and neuroinflammation leading to severe neurological symptoms. Lysoglycosphingolipids (lysoGSLs), also known to accumulate in the tissues of sphingolipidosis patients, exhibit cytotoxicity. LysoGSLs are the possible pathogenic cause, but the mechanisms are still unknown in detail. Here, we first show that lysoGSLs are potential inhibitors of phosphoinositide 3-kinase (PI3K) to reduce cell survival signaling. We found that phosphorylated Akt was commonly reduced in fibroblasts from patients with sphingolipidoses, including GM1/GM2 gangliosidoses and Gaucher's disease, suggesting the contribution of lysoGSLs to the pathogenesis. LysoGSLs caused  cell death and decreased the level of phosphorylated Akt as in the patient fibroblasts. Extracellularly administered lysoGM1 permeated ...

Source: Journal of Neurochemistry - November 18, 2023 Category: Neuroscience Authors: Ryosuke Watanabe, Daisuke Tsuji, Hiroki Tanaka, Michael Shintaro Uno, Yukiya Ohnishi, Shindai Kitaguchi, Tsuyoshi Matsugu, Ryuto Nakae, Hiromi Teramoto, Kei Yamamoto, Yasuo Shinohara, Takatsugu Hirokawa, Nozomu Okino, Makoto Ito, Kohji Itoh Tags: ORIGINAL ARTICLE Source Type: research