Lipotoxicity Downstream of α-Synuclein Imbalance: A Relevant Pathomechanism in Synucleinopathies?
Lipotoxicity Downstream of α-Synuclein Imbalance: A Relevant Pathomechanism in Synucleinopathies?
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DOI：
10.3390/biom12010040
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发表时间：
2021-12-28
期刊：
影响因子：
5.5
通讯作者：
Dettmer U
中科院分区：
文献类型：
--
作者：
Tripathi A;Fanning S;Dettmer U
帕金森病及相关脑疾病中的神经元丢失与丰富的神经元蛋白α-突触核蛋白（αS）密切相关。然而，令人惊讶的是，我们对αS在这些疾病中究竟如何发挥毒性的了解很少。已经提出了蛋白质毒性、紊乱的囊泡运输、线粒体功能障碍和其他毒性机制的假设，并且不同机制的组合似乎可能驱动病理学。近年来引起越来越多关注的毒性机制是α S相关的脂毒性。当脂肪酸超过代谢需要时，通常在细胞中发生脂毒性，从而触发流入非氧化代谢的有害途径。遗传和实验方法已经揭示了脂质储存障碍，最明显的是戈谢病和突触核蛋白病之间的显著重叠。脂质畸变导致突触核蛋白错误折叠以及αS过量和错误折叠导致脂质畸变的证据越来越多。这是否意味着突触核蛋白病的关键问题是脂毒性，有害脂质物质的积累或脂质平衡的改变？在这里，我们回顾了现有的文献，试图接近答案。
Neuronal loss in Parkinson’s disease and related brain diseases has been firmly linked to the abundant neuronal protein α-synuclein (αS). However, we have gained surprisingly little insight into how exactly αS exerts toxicity in these diseases. Hypotheses of proteotoxicity, disturbed vesicle trafficking, mitochondrial dysfunction and other toxicity mechanisms have been proposed, and it seems possible that a combination of different mechanisms may drive pathology. A toxicity mechanism that has caught increased attention in the recent years is αS-related lipotoxicity. Lipotoxicity typically occurs in a cell when fatty acids exceed the metabolic needs, triggering a flux into harmful pathways of non-oxidative metabolism. Genetic and experimental approaches have revealed a significant overlap between lipid storage disorders, most notably Gaucher’s disease, and synucleinopathies. There is accumulating evidence for lipid aberrations causing synuclein misfolding as well as for αS excess and misfolding causing lipid aberration. Does that mean the key problem in synucleinopathies is lipotoxicity, the accumulation of harmful lipid species or alteration in lipid equilibrium? Here, we review the existing literature in an attempt to get closer to an answer.
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影响因子：
2.9
作者：
Bodner, Christina R.;Maltsev, Alexander S.;Dobson, Christopher M.;Bax, Ad
通讯作者：
Bax, Ad
DOI：
10.3390/molecules25215053
发表时间：
2020-10-30
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Geltinger F;Schartel L;Wiederstein M;Tevini J;Aigner E;Felder TK;Rinnerthaler M
通讯作者：
Rinnerthaler M
影响因子：
4.5
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
通讯作者：
Mollereau B
影响因子：
168.9
作者：
Chartier-Harlin, MC;Kachergus, J;Destée, A
通讯作者：
Destée, A
影响因子：
9.9
作者：
Clark, L. N.;Ross, B. M.;Marder, K.
通讯作者：
Marder, K.