Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons located in the substantia nigra pars compacta and the presence of proteinaceous inclusions called Lewy bodies and Lewy neurites in numerous brain regions. Increasing evidence indicates that Lewy pathology progressively involves additional regions of the nervous system as the disease advances, and the prion‐like propagation of α‐synuclein (α‐syn) pathology promotes PD progression. Accordingly, the modulation of α‐syn transmission may be important for the development of disease‐modifying therapies in patients with PD. Here, we demonstrate that α‐syn fibrils induce c‐src activation in neurons, which depends on the FcγRIIb‐SHP‐1/‐2‐c‐src pathway and enhances signals for the uptake of α‐syn into neurons. Blockade of c‐src activation inhibits the uptake of α‐syn and the formation of Lewy body‐like inclusions. Furthermore, the blockade of c‐src activation also inhibits the release of α‐syn via activation of autophagy. The brain‐permeable c‐src inhibitor, saracatinib, efficiently reduces α‐syn propagation into neighboring regions in an in vivo model system. These results suggest a new therapeutic target against progressive PD.

中文翻译：

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c-src在α-突触核蛋白细胞间传递中的双重作用。

帕金森氏病（PD）的特征是位于黑质致密部的多巴胺能神经元丢失，并且在许多大脑区域都存在称为路易小体和路易神经突的蛋白质包裹体。越来越多的证据表明，路易氏病随着疾病的进展逐渐累及神经系统的其他区域，而α-突触核蛋白（α-syn）病理的病毒样传播促进了PD的进展。因此，α-syn传递的调节对于PD患者疾病改良疗法的发展可能很重要。在这里，我们证明了α-syn原纤维诱导神经元中的c-src激活，这取决于FcγRIIb-SHP-1/ 1-2-c-src途径并增强了α-syn被神经元摄取的信号。c-src激活的阻滞抑制了α-syn的摄取和路易体样夹杂物的形成。此外，对c-src激活的阻断还通过自噬激活抑制了α-syn的释放。脑可渗透的c-src抑制剂saracatinib可有效减少α-syn传播到邻近区域体内模型系统。这些结果表明了针对进行性PD的新治疗靶标。