Author:
Moors Tim E.,Maat Christina A.,Niedieker Daniel,Mona Daniel,Petersen Dennis,Timmermans-Huisman Evelien,Kole Jeroen,El-Mashtoly Samir F.,Spycher Liz,Zago Wagner,Barbour Robin,Mundigl Olaf,Kaluza Klaus,Huber Sylwia,Hug Melanie N.,Kremer Thomas,Ritter Mirko,Dziadek Sebastian,Geurts Jeroen J.G.,Gerwert Klaus,Britschgi Markus,van de Berg Wilma D.J.
Abstract
AbstractPost-translational modifications of alpha-synuclein (aSyn), particularly phosphorylation at Serine 129 (Ser129-p) and truncation of its C-terminus (CTT), have been implicated in Parkinson’s disease (PD) pathology. To gain more insight in the relevance of Ser129-p and CTT aSyn under physiological and pathological conditions, we investigated their subcellular distribution patterns in normal aged and PD brains using highly-selective antibodies in combination with 3D multicolor STED microscopy. We show that CTT aSyn localizes in mitochondria in PD patients and controls, whereas the organization of Ser129-p in a cytoplasmic network is strongly associated with pathology. Nigral Lewy bodies show an onion skin-like architecture, with a structured framework of Ser129-p aSyn and neurofilaments encapsulating CTT aSyn in their core, which displayed high content of proteins and lipids by label-free CARS microscopy. The subcellular phenotypes of antibody-labeled pathology identified in this study provide evidence for a crucial role of Ser129-p aSyn in Lewy body formation.
Publisher
Cold Spring Harbor Laboratory