Univ. Lille, Inserm, CHU Lille, UMR-S 1172-LilNCog-Lille Neuroscience and Cognition, F-59000 Lille, France.
Cells. 2021 Sep 17;10(9):2452. doi: 10.3390/cells10092452.
Since the initial identification of alpha-synuclein (α-syn) at the synapse, numerous studies demonstrated that α-syn is a key player in the etiology of Parkinson's disease (PD) and other synucleinopathies. Recent advances underline interactions between α-syn and lipids that also participate in α-syn misfolding and aggregation. In addition, increasing evidence demonstrates that α-syn plays a major role in different steps of synaptic exocytosis. Thus, we reviewed literature showing (1) the interplay among α-syn, lipids, and lipid membranes; (2) advances of α-syn synaptic functions in exocytosis. These data underscore a fundamental role of α-syn/lipid interplay that also contributes to synaptic defects in PD. The importance of lipids in PD is further highlighted by data showing the impact of α-syn on lipid metabolism, modulation of α-syn levels by lipids, as well as the identification of genetic determinants involved in lipid homeostasis associated with α-syn pathologies. While questions still remain, these recent developments open the way to new therapeutic strategies for PD and related disorders including some based on modulating synaptic functions.
自突触中首次鉴定出α-突触核蛋白（α-syn）以来，大量研究表明α-syn 是帕金森病（PD）和其他突触核蛋白病病因学的关键因素。最近的进展强调了α-syn 与脂质之间的相互作用，这些脂质也参与了α-syn 的错误折叠和聚集。此外，越来越多的证据表明，α-syn 在突触小泡胞吐的不同步骤中发挥重要作用。因此，我们回顾了文献，展示了（1）α-syn、脂质和脂膜之间的相互作用；（2）α-syn 在突触小泡胞吐中的突触功能的进展。这些数据强调了α-syn/脂质相互作用的基本作用，这也导致了 PD 中的突触缺陷。脂质在 PD 中的重要性进一步凸显了数据表明 α-syn 对脂质代谢的影响、脂质对 α-syn 水平的调节，以及与 α-syn 病理学相关的参与脂质动态平衡的遗传决定因素的鉴定。虽然仍有一些问题尚未解决，但这些最新的发展为 PD 和相关疾病的新治疗策略开辟了道路，包括一些基于调节突触功能的策略。
