Detailed structural orchestration of Lewy pathology in Parkinson's disease as revealed by 3D multicolor STED microscopy

Tim E. Moors, Christina A. Maat, Daniel Niedieker, Daniel Mona, Dennis Petersen, Evelien Timmermans-Huisman, Jeroen Kole, Samir F. El-Mashtoly, Wagner Zago, Robin Barbour, Olaf Mundigl, Klaus Kaluza, Sylwia Huber, Melanie N. Hug, Thomas Kremer, Mirko Ritter, Sebastian Dziadek, Jeroen J.G. Geurts, Klaus Gerwert, Markus BritschgiWilma D.J. van de Berg

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)470476
JournalBiorxiv
DOIs
Publication statusPublished - 2018

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