NDLI: Phosphorylation at S87 is enhanced in synucleinopathies, inhibits α-synuclein oligomerization and influences synuclein-membrane interactions

Content Provider	PubMed Central
Author	Paleologou, Katerina E. Oueslati, Abid Gideon, Shakked Rospigliosi, Carla C. Kim, Hai-young Lamberto, Gonzalo R. Fernandez, Claudio O. Schmid, Adrian Chegini, Fariba Gai, Wei Ping Chiappe, Diego Marc, Moniatte Schneider, Bernard L. Aebischer, Patrick Eliezer, David Markus, Zweckstetter Masliah, Eliezer Lashuel, Hilal A.
Abstract	Increasing evidence suggests that phosphorylation may play an important role in the oligomerization, fibrillogenesis, Lewy body (LB) formation and neurotoxicity of α-synuclein (α-syn) in Parkinson’s disease. Herein we demonstrate that α-syn is phosphorylated at S87 in vivo and within Lewy bodies. The levels of S87-P are increased in brains of transgenic (TG) models of synucleinopathies and human brains from Alzheimer’s disease (AD), Lewy body disease (LBD), and multiple system atrophy (MSA) patients. Using antibodies against phosphorylated α-syn (S129-P and S87-P), significant amount of immunoreactivity was detected in the membrane in the LBD, MSA and AD cases but not in normal controls. In brain homogenates from diseased human brains and TG animals, the majority of S87-P α-syn was detected in the membrane fractions. A battery of biophysical methods were used to dissect the effect of S87 phosphorylation on the structure, aggregation and membrane binding properties of monomeric α-syn. These studies demonstrated that phosphorylation at S87 expands the structure of α-syn, increases its conformational flexibility and blocks its fibrillization in vitro. Furthermore, phosphorylation at S87, but not S129, results in significant reduction of α-syn binding to membranes. Together, our findings provide novel mechanistic insight into the role of phosphorylation at S87 and S129 in the pathogenesis of synucleinopathies and potential roles of phosphorylation in α-syn normal biology.
Related Links	http://dx.doi.org/10.1523/jneurosci.5922-09.2010
Ending Page	3198
Page Count	15
Starting Page	3184
File Format	PDF
ISSN	02706474
e-ISSN	15292401
Journal	The Journal of neuroscience : the official journal of the Society for Neuroscience
Issue Number	9
Volume Number	30
Language	English
Publisher Date	2010-03-03
Access Restriction	Open
Subject Keyword	Neuroscience(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Neuroscience

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