Effects of Serine 129 Phosphorylation on alpha-Synuclein Aggregation, Membrane Association, and Internalization Journal Article

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Authors: Samuel, F.; Flavin, W. P.; Iqbal, S; Pacelli, C.; Sri Renganathan, S. D.; Trudeau, L. E.; Campbell, E. M.; Fraser, P. E.; Tandon, A.
Article Title: Effects of Serine 129 Phosphorylation on alpha-Synuclein Aggregation, Membrane Association, and Internalization
Abstract: Although trace levels of phosphorylated alpha-synuclein (alpha-syn) are detectable in normal brains, nearly all alpha-syn accumulated within Lewy bodies in Parkinson disease brains is phosphorylated on serine 129 (Ser-129). The role of the phosphoserine residue and its effects on alpha-syn structure, function, and intracellular accumulation are poorly understood. Here, co-expression of alpha-syn and polo-like kinase 2 (PLK2), a kinase that targets Ser-129, was used to generate phosphorylated alpha-syn for biophysical and biological characterization. Misfolding and fibril formation of phosphorylated alpha-syn isoforms were detected earlier, although the fibrils remained phosphatase- and protease-sensitive. Membrane binding of alpha-syn monomers was differentially affected by phosphorylation depending on the Parkinson disease-linked mutation. WT alpha-syn binding to presynaptic membranes was not affected by phosphorylation, whereas A30P alpha-syn binding was greatly increased, and A53T alpha-syn was slightly lower, implicating distal effects of the carboxyl- on amino-terminal membrane binding. Endocytic vesicle-mediated internalization of pre-formed fibrils into non-neuronal cells and dopaminergic neurons matched the efficacy of alpha-syn membrane binding. Finally, the disruption of internalized vesicle membranes was enhanced by the phosphorylated alpha-syn isoforms, a potential means for misfolded extracellular or lumenal alpha-syn to access cytosolic alpha-syn. Our results suggest that the threshold for vesicle permeabilization is evident even at low levels of alpha-syn internalization and are relevant to therapeutic strategies to reduce intercellular propagation of alpha-syn misfolding.
Journal Title: The Journal of biological chemistry
Volume: 291
Issue: 9
ISSN: 1083-351X; 0021-9258
Publisher: by The American Society for Biochemistry and Molecular Biology, Inc  
Journal Place: United States
Date Published: 2016
Start Page: 4374
End Page: 4385
Language: eng
DOI/URL:

10.1074/jbc.M115.705095
Notes: LR: 20160406; CI: (c) 2016; JID: 2985121R; OID: NLM: PMC4813466 [Available on 02/26/17]; OTO: NOTNLM; PMCR: 2017/02/26 00:00; 2015/11/17 [received]; 2015/12/30 [aheadofprint]; ppublish