TY - JOUR T1 - Detailed structural orchestration of Lewy pathology in Parkinson’s disease as revealed by 3D multicolor STED microscopy JF - bioRxiv DO - 10.1101/470476 SP - 470476 AU - Tim E. Moors AU - Christina A. Maat AU - Daniel Niedieker AU - Daniel Mona AU - Dennis Petersen AU - Evelien Timmermans-Huisman AU - Jeroen Kole AU - Samir F. El-Mashtoly AU - Wagner Zago AU - Robin Barbour AU - Olaf Mundigl AU - Klaus Kaluza AU - Sylwia Huber AU - Melanie N. Hug AU - Thomas Kremer AU - Mirko Ritter AU - Sebastian Dziadek AU - Jeroen J.G. Geurts AU - Klaus Gerwert AU - Markus Britschgi AU - Wilma D.J. van de Berg Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/11/14/470476.abstract N2 - Post-translational modifications of alpha-synuclein (aSyn), in particular phosphorylation at Serine 129 (Ser129-p) and truncation of its C-terminus (CTT), have been implicated in Parkinson’s disease (PD) pathophysiology. Although great interest has emerged for these species as potential biomarkers and therapeutic targets in PD, little is known about their (sub)cellular manifestation in the human brain. In this study, we mapped distribution patterns of Ser129-p and CTT aSyn in neurons with and without Lewy pathology. The combination of highly selective antibodies with multicolor STED microscopy allowed detailed phenotyping of subcellular neuropathology in PD. Nigral Lewy Bodies revealed an onion skin-like 3D architecture, with a framework of Ser129-p aSyn and neurofilaments encapsulating CTT and membrane-associated aSyn epitopes. Based on the identification of subcellular pathological phenotypes in this study we present a novel hypothesis for maturation stages of Lewy pathology and provide evidence for a key role for Ser129-p aSyn in Lewy inclusion formation. ER -