Lewy pathology in Parkinson’s disease consists of a crowded organellar membranous medley

Shahmoradian, S. H.; Genoud, C.; Graff-Meyer, A.; Hench, J.; Moors, T.; Schweighauser, G.; Wang, J.; Goldie, K. N.; Suetterlin, R.; Castano-Diez, D.; Perez-Navarro, P.; Huisman, E.; Ipsen, S.; Ingrassia, A.; de Gier, Y.; Rozemuller, A. J. M.; Da Paepe, A.; Erny, J.; Staempfli, A.; Hoernschemeyer, J.; Grosserueschkamp, F.; Niedieker, D.; El-Mashtoly, S. F.; Quadri, M.; van Ijcken, W. F. J.; Bonifati, V.; Gerwert, K.; Bohrmann, B.; Frank, S.; Britschgi, M.; Stahlberg, H.; van de Berg, W.; Lauer, M. E.

doi:10.1101/137976

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bioRxiv · 10.1101/137976

Lewy pathology in Parkinson’s disease consists of a crowded organellar membranous medley

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Abstract

Parkinsons 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 -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 Parkinsons disease brain donors, we identified -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 -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 Parkinsons patients a subcellular protein-lipid compartmentalization not previously described in Lewy pathology.

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Shahmoradian, S. H., Genoud, C., Graff-Meyer, A., Hench, J., Moors, T., Schweighauser, G., Wang, J., Goldie, K. N., Suetterlin, R., Castano-Diez, D., Perez-Navarro, P., Huisman, E., Ipsen, S., Ingrassia, A., de Gier, Y., Rozemuller, A. J. M., Da Paepe, A., Erny, J., Staempfli, A., Hoernschemeyer, J., Grosserueschkamp, F., Niedieker, D., El-Mashtoly, S. F., Quadri, M., van Ijcken, W. F. J., Bonifati, V., Gerwert, K., Bohrmann, B., Frank, S., Britschgi, M., Stahlberg, H., van de Berg, W., Lauer, M. E.. 2017-05-16. Lewy pathology in Parkinson’s disease consists of a crowded organellar membranous medley. https://doi.org/10.1101/137976

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