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- Title
Phosphorylation at S87 Is Enhanced in Synucleinopathies, Inhibits α-Synuclein Oligomerization, and Influences Synuclein-Membrane Interactions.
- Authors
Paleologou, Katerina E.; Oueslati, Abid; Shakked, Gideon; Rospigliosi, Carla C.; Hai-Young Kim; Lamberto, Gonzalo R.; Fernandez, Claudio O.; Schmid, Adrian; Chegini, Fariba; Wei Ping Gai; Chiappe, Diego; Moniatte, Marc; Schneider, Bernard L.; Aebischer, Patrick; Eliezer, David; Zweckstetter, Markus; 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 disease. Herein we demonstrate that α-syn is phosphorylated at S87 in vivo and within LBs. The levels of S87-P are increased in brains of transgenic (TG) models of synucleinopathies and human brains from Alzheimer disease (AD), LB disease (LBD), and multiple system atrophy (MSA) patients. Using antibodies against phosphorylated α-syn (S129-P and S87-P), a 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-Pα-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.
- Subjects
PHOSPHORYLATION; IMMUNOGLOBULINS; AMINO acid sequence; ALZHEIMER'S disease; LEWY body dementia; PARKINSON'S disease
- Publication
Journal of Neuroscience, 2010, Vol 30, Issue 9, p3184
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.5922-09.2010