Parkinson's disease genes VPS35 and EIF4G1 interact genetically and converge on alpha-synuclein

Parkinson's disease (PD) is a common human neurodegenerative movement disorder. Studies of the genetic forms of PD have helped to reveal disease mechanisms. Functional interactions between some Parkinson's disease (PD) genes, like PINK1 and parkin, have been identified, but whether other ones interact remains elusive. Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. We also show interactions between VPS35, EIF4G1 and alpha-synuclein, a protein with a key role in the pathogenesis of both sporadic and familial PD. We extend our findings from yeast to an animal model and show these interactions are conserved in neurons. We also connect VPS35 impairments to neurodegeneration in alpha-synuclein transgenic mice. Our studies reveal unexpected genetic and functional interactions between two seemingly unrelated PD genes and functionally connect them to alpha-synuclein pathobiology in yeast, worms, and mouse. Finally, we provide a resource of candidate PD genes for future genetic and functional interrogation. Ribosome profiling (RiboSeq) of wild type and VPS35 deletion yeast strains, with or without overexpression of the TIF4631 initiation factor

帕金森病（PD）是一类常见的人类神经退行性运动障碍。针对PD遗传亚型的研究有助于揭示其发病机制。目前已明确部分PD相关基因（如PINK1与parkin）之间存在功能相互作用，但其余基因间是否存在相互作用仍不明确。本研究报道了两种PD相关基因VPS35与EIF4G1之间此前未被发现的遗传相互作用。研究证实，EIF4G1的上调会引发与蛋白质错误折叠相关的功能缺陷。分拣蛋白（sortilin）的表达可在VPS35的下游通路中挽救上述缺陷，这提示分拣蛋白在PD中可能发挥潜在作用。本研究还证实VPS35、EIF4G1与α-突触核蛋白（alpha-synuclein）之间存在相互作用；α-突触核蛋白在散发性与家族性PD的发病机制中均发挥关键作用。本研究将实验结论从酵母模型拓展至动物模型，证实上述相互作用在神经元中同样保守存在。本研究还将VPS35功能缺陷与α-突触核蛋白转基因小鼠的神经退行性病变关联起来。本研究揭示了两种看似无关的PD相关基因之间此前未被发现的遗传与功能相互作用，并在酵母、线虫与小鼠模型中，将二者与α-突触核蛋白的病理生物学过程建立了功能关联。最后，本研究为未来的遗传与功能研究提供了一批候选PD相关基因资源。本数据集包含野生型与VPS35缺失酵母菌株（分别伴随或不伴随翻译起始因子TIF4631的过表达）的核糖体谱（RiboSeq）分析数据。