Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-University (FAU), Erlangen-Nürnberg, 91054 Erlangen, Germany.
Neuron. 2018 Oct 10;100(1):75-90.e5. doi: 10.1016/j.neuron.2018.09.014.
α-Synuclein (αS) regulates vesicle exocytosis but forms insoluble deposits in Parkinson's disease (PD). Developing disease-modifying therapies requires animal models that reproduce cardinal features of PD. We recently described a previously unrecognized physiological form of αS, α-helical tetramers, and showed that familial PD-causing missense mutations shift tetramers to aggregation-prone monomers. Here, we generated mice expressing the fPD E46K mutation plus 2 homologous E→K mutations in adjacent KTKEGV motifs. This tetramer-abrogating mutant causes phenotypes similar to PD. αS monomers accumulate at membranes and form vesicle-rich inclusions. αS becomes insoluble, proteinase K-resistant, Ser129-phosphorylated, and C-terminally truncated, as in PD. These changes affect regions controlling motor behavior, including a decrease in nigrostriatal dopaminergic neurons. The outcome is a progressive motor syndrome including tremor and gait and limb deficits partially responsive to L-DOPA. This fully penetrant phenotype indicates that tetramers are required for normal αS homeostasis and that chronically shifting tetramers to monomers may result in PD, with attendant therapeutic implications.
α-突触核蛋白（αS）调节囊泡胞吐，但在帕金森病（PD）中形成不溶性沉积物。开发疾病修饰疗法需要能够重现 PD 主要特征的动物模型。我们最近描述了一种以前未被识别的 αS 生理形式，即α-螺旋四聚体，并表明家族性 PD 致病错义突变会将四聚体转变为易于聚集的单体。在这里，我们生成了表达 fPD E46K 突变和相邻 KTKEGV 基序中 2 个同源 E→K 突变的小鼠。这种破坏四聚体的突变体引起与 PD 相似的表型。αS 单体在膜上积累并形成富含囊泡的内含物。αS 变得不溶，对蛋白水解酶有抗性，Ser129 磷酸化，并在 C 端截断，如 PD 中一样。这些变化影响控制运动行为的区域，包括黑质纹状体多巴胺能神经元减少。结果是一种进行性运动综合征，包括震颤和步态及肢体缺陷，部分对 L-DOPA 有反应。这种完全穿透的表型表明四聚体对于正常的 αS 内稳态是必需的，并且将四聚体慢性转变为单体可能导致 PD，这具有相关的治疗意义。
