Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115 USA.
Sci Signal. 2023 Feb 14;16(772):eadd7220. doi: 10.1126/scisignal.add7220.
Synaptotagmin-11 (Syt11) is a vesicle-trafficking protein that is linked genetically to Parkinson's disease (PD). Likewise, the protein α-synuclein regulates vesicle trafficking, and its abnormal aggregation in neurons is the defining cytopathology of PD. Because of their functional similarities in the same disease context, we investigated whether the two proteins were connected. We found that Syt11 was palmitoylated in mouse and human brain tissue and in cultured cortical neurons and that this modification to Syt11 disrupted α-synuclein homeostasis in neurons. Palmitoylation of two cysteines adjacent to the transmembrane domain, Cys and Cys, localized Syt11 to digitonin-insoluble portions of intracellular membranes and protected it from degradation by the endolysosomal system. In neurons, palmitoylation of Syt11 increased its abundance and enhanced the binding of α-synuclein to intracellular membranes. As a result, the abundance of the physiologic tetrameric form of α-synuclein was decreased, and that of its aggregation-prone monomeric form was increased. These effects were replicated by overexpression of wild-type Syt11 but not a palmitoylation-deficient mutant. These findings suggest that palmitoylation-mediated increases in Syt11 amounts may promote pathological α-synuclein aggregation in PD.
突触结合蛋白 11（Syt11）是一种与帕金森病（PD）相关的囊泡运输蛋白。同样，α-突触核蛋白调节囊泡运输，其在神经元中的异常聚集是 PD 的特征性细胞学病理学改变。由于它们在相同疾病背景下具有相似的功能，我们研究了这两种蛋白是否存在关联。我们发现 Syt11 在小鼠和人脑组织以及培养的皮质神经元中发生棕榈酰化，这种 Syt11 的修饰破坏了神经元中α-突触核蛋白的内稳态。位于跨膜结构域附近的两个半胱氨酸（Cys 和 Cys）的棕榈酰化将 Syt11 定位到细胞内膜的不溶性部分，并使其免受内体溶酶体系统的降解。在神经元中，Syt11 的棕榈酰化增加了其丰度，并增强了α-突触核蛋白与细胞内膜的结合。结果，生理四聚体形式的α-突触核蛋白的丰度降低，其易于聚集的单体形式的丰度增加。野生型 Syt11 的过表达可以复制这些效应，但棕榈酰化缺陷突变体则不行。这些发现表明，Syt11 含量的棕榈酰化介导增加可能促进 PD 中病理性α-突触核蛋白的聚集。
