Subcellular orchestration of alpha-synuclein variants in Parkinson’s disease brains revealed by 3D multicolor STED microscopy
Moors, T. E.; Maat, C. A.; Niedieker, D.; Mona, D.; Petersen, D.; Timmermans-Huisman, E.; Kole, J.; El-Mashtoly, S. F.; Spycher, L.; Zago, W.; Barbour, R.; Mundigl, O.; Kaluza, K.; Huber, S.; Hug, M. N.; Kremer, T.; Ritter, M.; Dziadek, S.; Geurts, J. J. G.; Gerwert, K.; Britschgi, M.; van de Berg, W. D. J.
Show abstract
Post-translational modifications of alpha-synuclein (aSyn), particularly phosphorylation at Serine 129 (Ser129-p) and truncation of its C-terminus (CTT), have been implicated in Parkinsons 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.
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