Systemic α-synuclein injection triggers selective neuronal pathology as seen in patients with Parkinson's disease.,Molecular Psychiatry

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Systemic α-synuclein injection triggers selective neuronal pathology as seen in patients with Parkinson's disease.
Molecular Psychiatry ( IF 9.6 ) Pub Date : 2019-11-22 , DOI: 10.1038/s41380-019-0608-9
Wei-Li Kuan ₁ , Katherine Stott ₂ , Xiaoling He ₁ , Tobias C Wood ₃ , Sujeong Yang ₁ , Jessica C F Kwok _{1,

4,

5} , Katie Hall ₁ , Yanyan Zhao ₆ , Ole Tietz ₆ , Franklin I Aigbirhio ₆ , Anthony C Vernon _{7,

8} , Roger A Barker _{1,

9,

10}

Affiliation

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.
Department of Neuroimaging, Kings College London, London, SE5 8AF, UK.
School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
Centre for Reconstructive Neuroscience, Institute of Experimental Medicine, 142 20, Prague 4, Czech Republic.
Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ, UK.
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 9RX, UK.
MRC Centre for Neurodevelopmental Disorders, King's College London, London, SE1 1UL, UK.
Department of Neurology, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
Wellcome Trust-MRC Cambridge Stem Cell Centre, Cambridge, CB2 1QR, UK.

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.

中文翻译：

如帕金森病患者所见，全身性 α-突触核蛋白注射会触发选择性神经元病理学。

帕金森病 (PD) 是一种 α-突触核蛋白病，其特征是特定神经元群体的进行性丧失。在这里，我们开发了一种新方法来经血管递送具有复杂四级结构的蛋白质，包括 α-突触核蛋白预制原纤维 (pff)。我们表明，单次全身给药 α-突触核蛋白 pff 会触发非转基因大鼠内源性 α-突触核蛋白的病理转化，从而导致离散大脑区域的神经变性。具体而言，暴露于 pff 的动物表现出胃肠和嗅觉功能的进行性恶化，这与中枢和肠神经系统中细胞病理学的存在相对应。产生的 α-突触核蛋白病理学既具有时间依赖性又具有区域特异性。有趣的是，在 PD 早期受影响的大脑区域中观察到最显着的神经病理学变化。因此，我们的数据首次证明，单次经血管给药 α-突触核蛋白 pff 可导致类似于特发性 PD 运动前阶段的选择性区域神经病理学。此外，这种新型递送方法还可用于将一系列其他致病性和治疗性蛋白质货物经血管递送至大脑。

更新日期：2019-11-22

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