Mapping the Subcellular Distribution of α-Synuclein in Neurons using Genetically Encoded Probes for Correlated Light and Electron Microscopy: Implications for Parkinson's Disease Pathogenesis

摘要: Modifications to the gene encoding human α-synuclein have been linked development of Parkinson's disease. The highly conserved structure suggests a functional interaction with membranes, and several lines evidence point role in vesicle-related processes within nerve terminals. Using recombinant fusions α-synuclein, including new genetic tags developed for correlated light microscopy electron (the tetracysteine-biarsenical labeling system or fluorescent protein microscopy, MiniSOG), we determined distribution when overexpressed primary neurons at supramolecular cellular scales three dimensions (3D). We observed specific association large otherwise poorly characterized membranous organelle presynaptic terminal, as well smaller vesicular structures these boutons. Furthermore, was localized multiple elements degradation pathway, multivesicular bodies axons lysosomes neuronal cell bodies. Examination synapses brains transgenic mice overexpressing revealed alterations endomembrane systems similar our findings culture. Three-dimensional tomographic analysis enlarged terminals brain areas that were filled membrane-bounded organelles, tubulovesicular what vitro. propose overexpression is associated hypertrophy membrane terminal previously shown vesicle recycling. Our data support conclusion involved sorting, channeling, packaging, transport synaptic material destined degradation.