Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, Basel, Switzerland.
Department of Biology and Chemistry, Paul Scherrer Institute, Villigen, Switzerland.
Nat Neurosci. 2019 Jul;22(7):1099-1109. doi: 10.1038/s41593-019-0423-2. Epub 2019 Jun 24.
Parkinson's disease, the most common age-related movement disorder, is a progressive neurodegenerative disease with unclear etiology. Key neuropathological hallmarks are Lewy bodies and Lewy neurites: neuronal inclusions immunopositive for the protein α-synuclein. In-depth ultrastructural analysis of Lewy pathology is crucial to understanding pathogenesis of this disease. Using correlative light and electron microscopy and tomography on postmortem human brain tissue from Parkinson's disease brain donors, we identified α-synuclein immunopositive Lewy pathology and show a crowded environment of membranes therein, including vesicular structures and dysmorphic organelles. Filaments interspersed between the membranes and organelles were identifiable in many but not all α-synuclein inclusions. Crowding of organellar components was confirmed by stimulated emission depletion (STED)-based super-resolution microscopy, and high lipid content within α-synuclein immunopositive inclusions was corroborated by confocal imaging, Fourier-transform coherent anti-Stokes Raman scattering infrared imaging and lipidomics. Applying such correlative high-resolution imaging and biophysical approaches, we discovered an aggregated protein-lipid compartmentalization not previously described in the Parkinsons' disease brain.
帕金森病是最常见的与年龄相关的运动障碍，是一种进行性神经退行性疾病，其病因尚不清楚。关键的神经病理学特征是路易体和路易神经突：神经元内包含免疫阳性的α-突触核蛋白。深入研究路易体病理学对于理解这种疾病的发病机制至关重要。我们使用帕金森病脑捐献者死后人脑组织的共聚焦和电子显微镜断层扫描，鉴定了α-突触核蛋白免疫阳性的路易体病理学，并显示了其中拥挤的膜环境，包括囊泡结构和畸形细胞器。在许多但不是所有的α-突触核蛋白包涵体中都可以识别出穿插在膜和细胞器之间的纤维。受激发射损耗（STED）的基于超分辨率显微镜证实了细胞器成分的拥挤，共聚焦成像、傅立叶变换相干反斯托克斯拉曼散射红外成像和脂质组学证实了α-突触核蛋白免疫阳性包涵体中含有高脂质含量。通过应用这种相关的高分辨率成像和生物物理方法，我们发现了帕金森病脑中以前未描述的聚集蛋白-脂质分隔化。
