@article {Shahmoradian137976, author = {Sarah H. Shahmoradian and Amanda J. Lewis and Christel Genoud and J{\"u}rgen Hench and Tim Moors and Paula P. Navarro and Daniel Casta{\~n}o-D{\'\i}ez and Gabriel Schweighauser and Alexandra Graff-Meyer and Kenneth N. Goldie and Rosmarie S{\"u}tterlin and Evelien Huisman and Angela Ingrassia and Yvonne de Gier and Annemieke J.M. Rozemuller and Jing Wang and Anne De Paepe and Johannes Erny and Andreas Staempfli and Joerg Hoernschemeyer and Frederik Gro{\ss}er{\"u}schkamp and Daniel Niedieker and Samir F. El-Mashtoly and Marialuisa Quadri and Wilfred F.J. van IJcken and Vincenzo Bonifati and Klaus Gerwert and Bernd Bohrmann and Stephan Frank and Markus Britschgi and Henning Stahlberg and Wilma D. J. van de Berg and Matthias E. Lauer}, title = {Lewy pathology in Parkinson{\textquoteright}s disease consists of a crowded organellar, membranous medley}, elocation-id = {137976}, year = {2019}, doi = {10.1101/137976}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Parkinson{\textquoteright}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, which are neuronal inclusions that are immunopositive for the protein α-synuclein. In-depth ultrastructural analysis of this Lewy pathology is crucial to understanding pathogenesis and progression of the disease. Using correlative light and electron microscopy/tomography on brain tissue from five Parkinson{\textquoteright}s disease brain donors, we identified α-synuclein immunopositive Lewy pathology and could show that the majority of these features including Lewy bodies and Lewy neurites primarily consists of a crowded membranous medley of vesicular structures and dysmorphic organelles. Only a small fraction of observed Lewy bodies contained predominant proteinaceous filaments, as previously described. The crowding of organellar components was confirmed by STED- based super-resolution microscopy, and high lipid content within the α-synuclein immunopositive inclusions was corroborated by confocal imaging, CARS/FTIR imaging and lipidomics. Applying this correlative high-resolution imaging and biophysical approach, we discovered in the postmortem brain of Parkinson{\textquoteright}s patients a subcellular protein-lipid compartmentalization not previously described in Lewy pathology.}, URL = {https://www.biorxiv.org/content/early/2019/02/13/137976}, eprint = {https://www.biorxiv.org/content/early/2019/02/13/137976.full.pdf}, journal = {bioRxiv} }