Kuan Wei-Li, Stott Katherine, He Xiaoling, Wood Tobias C, Yang Sujeong, Kwok Jessica C F, Hall Katie, Zhao Yanyan, Tietz Ole, Aigbirhio Franklin I, Vernon Anthony C, Barker Roger A
John van Geest Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, CB2 0PY, UK.
Department of Biochemistry, University of Cambridge, Cambridge, CB2 1GA, UK.
Mol Psychiatry. 2021 Feb;26(2):556-567. doi: 10.1038/s41380-019-0608-9. Epub 2019 Nov 22.
Parkinson's disease (PD) is an α-synucleinopathy characterized by the progressive loss of specific neuronal populations. Here, we develop a novel approach to transvascularly deliver proteins of complex quaternary structures, including α-synuclein preformed fibrils (pff). We show that a single systemic administration of α-synuclein pff triggers pathological transformation of endogenous α-synuclein in non-transgenic rats, which leads to neurodegeneration in discrete brain regions. Specifically, pff-exposed animals displayed a progressive deterioration in gastrointestinal and olfactory functions, which corresponded with the presence of cellular pathology in the central and enteric nervous systems. The α-synuclein pathology generated was both time dependent and region specific. Interestingly, the most significant neuropathological changes were observed in those brain regions affected in the early stages of PD. Our data therefore demonstrate for the first time that a single, transvascular administration of α-synuclein pff can lead to selective regional neuropathology resembling the premotor stage of idiopathic PD. Furthermore, this novel delivery approach could also be used to deliver a range of other pathogenic, as well as therapeutic, protein cargos transvascularly to the brain.
帕金森病（PD）是一种以特定神经元群体进行性丧失为特征的α-突触核蛋白病。在此，我们开发了一种经血管递送具有复杂四级结构蛋白质的新方法，包括α-突触核蛋白预形成纤维（pff）。我们表明，单次全身给予α-突触核蛋白pff可引发非转基因大鼠内源性α-突触核蛋白的病理转化，进而导致离散脑区的神经变性。具体而言，暴露于pff的动物在胃肠和嗅觉功能方面出现进行性恶化，这与中枢和肠神经系统中细胞病理学的存在相一致。所产生的α-突触核蛋白病理学具有时间依赖性和区域特异性。有趣的是，在帕金森病早期受影响的那些脑区观察到了最显著的神经病理学变化。因此，我们的数据首次证明，单次经血管给予α-突触核蛋白pff可导致类似于特发性帕金森病运动前期的选择性区域神经病理学。此外，这种新的递送方法还可用于经血管向脑递送一系列其他致病以及治疗性蛋白质货物。
