Abnormal accumulation of lipid droplets in neurons induces the conversion of alpha-Synuclein to proteolytic resistant forms in a Drosophila model of Parkinson's disease.
Abnormal accumulation of lipid droplets in neurons induces the conversion of alpha-Synuclein to proteolytic resistant forms in a Drosophila model of Parkinson's disease.
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DOI：
10.1371/journal.pgen.1009921
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发表时间：
2021-11
期刊：
影响因子：
4.5
通讯作者：
Mollereau B
中科院分区：
文献类型：
--
作者：
Girard V;Jollivet F;Knittelfelder O;Celle M;Arsac JN;Chatelain G;Van den Brink DM;Baron T;Shevchenko A;Kühnlein RP;Davoust N;Mollereau B
帕金森病（Parkinson's disease，PD）是一种以α-突触核蛋白（α-synuclein，αSyn）聚集为特征的神经退行性疾病，与脂质代谢异常有关。在PD的细胞模型中观察到脂质在称为脂滴（LD）的细胞质细胞器中的积累。为了研究αSyn与调节LD稳态的蛋白质之间相互作用的病理生理学后果，我们使用了PD的转基因果蝇模型，其中人αSyn在感光神经元中特异性表达。我们首先发现，LD包被蛋白Perilipin 1或2（dPlin 1/2）的过度表达，限制了脂肪酶对LD的访问，显着增加了神经元中的三酰甘油（TG）负载LD。然而，dPlin诱导的LD在神经元中是独立的脂质合成代谢（二酰基甘油酰基转移酶1/中途，脂肪酸转运蛋白/dFatp）和分解代谢（布鲁默TG脂肪酶）酶，表明替代机制调节神经元LD稳态。有趣的是，由各种LD蛋白（dPlin 1，dPlin 2，CG 7900或KlarsichtLD-BD）诱导的LD积累通过αSyn的共表达协同放大，αSyn定位于果蝇感光神经元和人神经母细胞瘤细胞中的LD。最后，LD的积累增加了αSyn对蛋白水解消化的抗性，这是αSyn在人类神经元中聚集的特征。我们认为αSyn与LD蛋白协同作用抑制脂解，αSyn与LD的结合导致了αSyn在神经元中的致病性错误折叠和聚集。帕金森病（Parkinson's disease，PD）是一种以α-突触核蛋白（α-synuclein，αSyn）的神经毒性聚集为特征的神经退行性疾病。该疾病的细胞模型也与脂滴（LD）形式的异常脂肪储存有关。然而，LD在生物体中积聚在哪些细胞、神经元或神经胶质细胞中仍然未知。为了了解αSyn与LD积累之间的关系，我们使用了PD的果蝇（果蝇）模型。我们发现，在存在一种蛋白质，包被LD，周脂蛋白，LD积累在感光神经元的苍蝇。有趣的是，在αSyn存在下，由周脂蛋白或其他LD包被蛋白诱导的LD积累增强。利用人神经细胞系和果蝇，我们可以证明LD-包被蛋白和αSyn蛋白定位于LD表面。最后，我们观察到，αSyn聚集的过程中，LD的存在下，通过使用生化方法增强。因此，我们认为αSyn与LD的相关性可能有助于αSyn聚集和病理进展。
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by alpha-synuclein (αSyn) aggregation and associated with abnormalities in lipid metabolism. The accumulation of lipids in cytoplasmic organelles called lipid droplets (LDs) was observed in cellular models of PD. To investigate the pathophysiological consequences of interactions between αSyn and proteins that regulate the homeostasis of LDs, we used a transgenic Drosophila model of PD, in which human αSyn is specifically expressed in photoreceptor neurons. We first found that overexpression of the LD-coating proteins Perilipin 1 or 2 (dPlin1/2), which limit the access of lipases to LDs, markedly increased triacylglyclerol (TG) loaded LDs in neurons. However, dPlin-induced-LDs in neurons are independent of lipid anabolic (diacylglycerol acyltransferase 1/midway, fatty acid transport protein/dFatp) and catabolic (brummer TG lipase) enzymes, indicating that alternative mechanisms regulate neuronal LD homeostasis. Interestingly, the accumulation of LDs induced by various LD proteins (dPlin1, dPlin2, CG7900 or KlarsichtLD-BD) was synergistically amplified by the co-expression of αSyn, which localized to LDs in both Drosophila photoreceptor neurons and in human neuroblastoma cells. Finally, the accumulation of LDs increased the resistance of αSyn to proteolytic digestion, a characteristic of αSyn aggregation in human neurons. We propose that αSyn cooperates with LD proteins to inhibit lipolysis and that binding of αSyn to LDs contributes to the pathogenic misfolding and aggregation of αSyn in neurons. Parkinson’s disease (PD) is a neurodegenerative disease characterized by the neurotoxic aggregation of the alpha-synuclein (αSyn) protein. Cellular models of the disease are also associated with an abnormal fat storage in the form of lipid droplets (LDs). However, in which cells, neuron or glial cells, LDs accumulate in the organism remains unknown. To understand the relationship between αSyn and the accumulation of LDs, we used a Drosophila (fruit fly) model of PD. We found that, in the presence of a protein that coats LDs, perilipin, LDs accumulate in photoreceptor neurons of the fly. Interestingly, the accumulation of LDs induced by perilipin or other LD-coating proteins was enhanced in the presence of αSyn. Using human neuronal cell lines and the fly, we could show that LD-coating and αSyn proteins localize at the surface of LDs. Finally, we observed that the process of αSyn aggregation was enhanced in the presence of LDs by using a biochemical approach. We thus propose that the association of αSyn with LDs could contribute to αSyn aggregation and progression of the pathology.
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影响因子：
64.5
作者：
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作者：
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影响因子：
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