TY - JOUR
T1 - Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes
AU - Shahmoradian, Sarah H.
AU - Lewis, Amanda J.
AU - Genoud, Christel
AU - Hench, Jürgen
AU - Moors, Tim E.
AU - Navarro, Paula P.
AU - Castaño-Díez, Daniel
AU - Schweighauser, Gabriel
AU - Graff-Meyer, Alexandra
AU - Goldie, Kenneth N.
AU - Sütterlin, Rosmarie
AU - Huisman, Evelien
AU - Ingrassia, Angela
AU - Gier, Yvonne de
AU - Rozemuller, Annemieke J.M.
AU - Wang, Jing
AU - Paepe, Anne De
AU - Erny, Johannes
AU - Staempfli, Andreas
AU - Hoernschemeyer, Joerg
AU - Großerüschkamp, Frederik
AU - Niedieker, Daniel
AU - El-Mashtoly, Samir F.
AU - Quadri, Marialuisa
AU - Van IJcken, Wilfred F.J.
AU - Bonifati, Vincenzo
AU - Gerwert, Klaus
AU - Bohrmann, Bernd
AU - Frank, Stephan
AU - Britschgi, Markus
AU - Stahlberg, Henning
AU - Van de Berg, Wilma D.J.
AU - Lauer, Matthias E.
N1 - Funding Information:
We are grateful to the individuals who participated in the brain donation program and their families, making this study possible. We thank S. Ipsen from the University Hospital Basel and S. Bichet from the Friedrich Miescher Institute for training and assisting with the immunohistochemistry, A. Fecteau-LeFebvre for electron microscopy maintenance, A. Jonker for help with preparing cryostat-cut tissue sections, Prothena for providing the pSer129 11A5 antibody, Advanced Optical Microscopy Core O|2 (www.ao2m.amsterdam) for support with STED imaging, D. Mona for help with labeling antibodies, P. Baumgartner and K. Bergmann for administrative help, and S. Müller for carefully proof-reading and editing the manuscript. S.H.S. was supported by the Roche Postdoctoral Fellowship (RPF) program; this work was in part supported by the Swiss National Science Foundation (SNF Grants no. CRSII3_154461 and CRSII5_177195), the Synapsis Foundation Switzerland, the foundation Heidi Seiler-Stiftung, and the Stichting Parkinson Fonds, the Netherlands.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/7/1
Y1 - 2019/7/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41593-019-0423-2
DO - 10.1038/s41593-019-0423-2
M3 - Article
C2 - 31235907
AN - SCOPUS:85067840164
SN - 1097-6256
VL - 22
SP - 1099
EP - 1109
JO - Nature neuroscience
JF - Nature neuroscience
IS - 7
ER -