The toxicities of A30P and A53T α-synuclein fibrils can be uniquely altered by the length and saturation of fatty acids in phosphatidylserine.
The toxicities of A30P and A53T α-synuclein fibrils can be uniquely altered by the length and saturation of fatty acids in phosphatidylserine.
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DOI：
10.1016/j.jbc.2023.105383
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发表时间：
2023-12
影响因子：
4.8
通讯作者：
Kurouski, Dmitry
中科院分区：
文献类型：
--
作者：
Ali, Abid;Zhaliazka, Kiryl;Dou, Tianyi;Holman, Aidan P.;Kurouski, Dmitry
中脑、下丘脑和丘脑的多巴胺能神经元进行性变性是帕金森病（PD）的标志。神经元死亡与α-突触核蛋白（α-syn）的突然聚集有关，α-突触核蛋白是一种调节突触间隙中囊泡运输的小蛋白。对有PD病史的家族的研究显示，α-syn的几个突变，包括A30P和A53T，与这种病理的早期发病有关。大量证据表明，脂质可以改变蛋白质聚集的速率，也可以改变淀粉样蛋白低聚物和原纤维的二级结构和毒性。然而，脂质在α-syn突变体稳定性中的作用尚不清楚。在本研究中，我们研究了磷脂酰丝氨酸（PS）对WT、A30P和A53T α-syn稳定性的影响。磷脂酰丝氨酸是一种阴离子脂质，在巨噬细胞对凋亡细胞的识别中起重要作用。我们发现不同长度的PS和脂肪酸饱和度加快了WT和A30P的聚集速度。同时，大多数PS对A53T的作用正好相反。我们还发现，不同长度和脂肪酸饱和度的PS改变了WT、A30P和A53T原纤维的二级结构和毒性。这些结果表明，脂质在家族性PD的发病和扩散中起重要作用。
Progressive degeneration of dopaminergic neurons in the midbrain, hypothalamus, and thalamus is a hallmark of Parkinson’s disease (PD). Neuronal death is linked to the abrupt aggregation of α-synuclein (α-syn), a small protein that regulates vesicle trafficking in synaptic clefts. Studies of families with a history of PD revealed several mutations in α-syn including A30P and A53T that are linked to the early onset of this pathology. Numerous pieces of evidence indicate that lipids can alter the rate of protein aggregation, as well as modify the secondary structure and toxicity of amyloid oligomers and fibrils. However, the role of lipids in the stability of α-syn mutants remains unclear. In this study, we investigate the effect of phosphatidylserine (PS), an anionic lipid that plays an important role in the recognition of apoptotic cells by macrophages, in the stability of WT, A30P, and A53T α-syn. We found PS with different lengths and saturation of fatty acids accelerated the rate of WT and A30P aggregation. At the same time, the opposite effect was observed for most PS on A53T. We also found that PS with different lengths and saturation of fatty acids change the secondary structure and toxicities of WT, A30P, and A53T fibrils. These results indicate that lipids can play an important role in the onset and spread of familial PD.
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影响因子：
5
作者：
Dou, Tianyi;Kurouski, Dmitry
通讯作者：
Kurouski, Dmitry
影响因子：
4.8
作者：
Lemkau, Luisel R.;Comellas, Gemma;Rienstra, Chad M.
通讯作者：
Rienstra, Chad M.
影响因子：
4.6
作者：
Hoffmann, Anna-Carin;Minakaki, Georgia;Xiang, Wei
通讯作者：
Xiang, Wei
DOI：
10.1073/pnas.97.2.571
发表时间：
2000-01-18
影响因子：
11.1
作者：
Conway, KA;Lee, SJ;Lansbury, PT
通讯作者：
Lansbury, PT
影响因子：
5.9
作者：
Harris, Meghan K.;Shneyder, Natalya;Minagar, Alireza
通讯作者：
Minagar, Alireza