α-synuclein (α-syn) accumulation and aggregation is a common pathological factor found in synucleinopathies, a group of neurodegenerative disorders that includes Parkinson´s disease (PD). It has been proposed that lipid dyshomeostasis is responsible for the occurrence of PD-related processes, however, the precise role of lipids in the onset and progression of neurodegenerative disorders remains unclear. Our aim was to investigate the effect of α-syn overexpression on neutral lipid metabolism and how this impacts on neuronal fate. We found lipid droplet (LD) accumulation in cells overexpressing α-syn to be associated with a rise in triacylglycerol (TAG) and cholesteryl ester (CE) levels. α-syn overexpression promoted diacylglycerol acyltransferase 2 upregulation and acyl-CoA synthetase activation, triggering TAG buildup, that was accompanied by an increase in diacylglycerol acylation. Moreover, the CE increment was associated with higher activity of acyl-CoA:cholesterol acyltransferase. Interestingly, α-syn overexpression increased cholesterol lysosomal accumulation. We observed that sterol regulatory element-binding protein (SREBP)-1 and SREBP-2 were differentially regulated by α-syn overexpression. The latter gave rise to a reduction in SREBP-1 nuclear translocation and consequently in fatty acid synthase expression, whereas it produced an increase in SREBP-2 nuclear localization. Surprisingly, and despite increased cholesterol levels, SREBP-2 downstream genes related to cholesterolgenesis were not upregulated as expected. Notably, phospholipid (PL) levels were diminished in cells overexpressing α-syn. This decrease was related to the activation of phospholipase A2 (PLA2) with a concomitant imbalance of the PL deacylation-acylation cycle. Fatty acids released from PLs by iPLA2 and cPLA2 action were esterified into TAGs, thus promoting a biological response to α-syn overexpression with uncompromised cell viability. When the described steady-state was disturbed under conditions favoring higher levels of α-syn, the response was an enhanced LD accumulation, this imbalance ultimately leading to neuronal death.

α-突触核蛋白 (α-syn) 积累和聚集是突触核蛋白病中常见的病理因素，突触核蛋白病是一组神经退行性疾病，包括帕金森病 (PD)。有人提出脂质失调是 PD 相关过程发生的原因，然而，脂质在神经退行性疾病的发生和进展中的确切作用仍不清楚。我们的目的是研究 α-syn 过表达对中性脂质代谢的影响以及这如何影响神经元命运。我们发现过度表达 α-syn 的细胞中的脂滴 (LD) 积累与甘油三酯 (TAG) 和胆固醇酯 (CE) 水平的升高有关。α-syn 过表达促进二酰基甘油酰基转移酶 2 上调和酰基辅酶 A 合成酶激活，触发 TAG 积累，伴随着二酰基甘油酰化的增加。此外，CE 增加与酰基辅酶 A：胆固醇酰基转移酶的更高活性有关。有趣的是，α-syn 过表达增加了胆固醇溶酶体的积累。我们观察到甾醇调节元件结合蛋白 (SREBP)-1 和 SREBP-2 受α-syn 过表达的差异调节。后者导致 SREBP-1 核易位减少，从而导致脂肪酸合酶表达减少，而它导致 SREBP-2 核定位增加。令人惊讶的是，尽管胆固醇水平升高，但与胆固醇生成相关的 SREBP-2 下游基因并未如预期的那样上调。值得注意的是，在过表达 α-syn 的细胞中，磷脂 (PL) 水平降低。这种减少与磷脂酶 A2 (PLA2) 的激活以及 PL 脱酰-酰化循环的伴随失衡有关。通过 iPLA2 和 cPLA2 作用从 PLs 释放的脂肪酸被酯化为 TAGs，从而促进对 α-syn 过表达的生物反应，同时保持细胞活力。当所描述的稳态在有利于更高水平 α-syn 的条件下受到干扰时，反应是增强的 LD 积累，这种不平衡最终导致神经元死亡。