title: Phosphorylation at S87 is enhanced in synucleinopathies, inhibits alpha-synuclein oligomerization, and influences synuclein-membrane interactions.
abstract: Increasing evidence suggests that phosphorylation may play an important role in the oligomerization, fibrillogenesis, Lewy body (LB) formation, and neurotoxicity of alpha-synuclein (alpha-syn) in Parkinson disease. Herein we demonstrate that alpha-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 alpha-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-P alpha-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 alpha-syn. These studies demonstrated that phosphorylation at S87 expands the structure of alpha-syn, increases its conformational flexibility, and blocks its fibrillization in vitro. Furthermore, phosphorylation at S87, but not S129, results in significant reduction of alpha-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 alpha-syn normal biology.
authors.affiliation: Laboratory of Molecular Neurobiology and Neuroproteomics, Brain Mind Institute, EPFL, Lausanne, Switzerland.
authors.forename: Katerina E
authors.initials: KE
authors.lastname: Paleologou
authors.forename: Abid
authors.initials: A
authors.lastname: Oueslati
authors.forename: Gideon
authors.initials: G
authors.lastname: Shakked
authors.forename: Carla C
authors.initials: CC
authors.lastname: Rospigliosi
authors.forename: Hai-Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Gonzalo R
authors.initials: GR
authors.lastname: Lamberto
authors.forename: Claudio O
authors.initials: CO
authors.lastname: Fernandez
authors.forename: Adrian
authors.initials: A
authors.lastname: Schmid
authors.forename: Fariba
authors.initials: F
authors.lastname: Chegini
authors.forename: Wei Ping
authors.initials: WP
authors.lastname: Gai
authors.forename: Diego
authors.initials: D
authors.lastname: Chiappe
authors.forename: Marc
authors.initials: M
authors.lastname: Moniatte
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Schneider
authors.forename: Patrick
authors.initials: P
authors.lastname: Aebischer
authors.forename: David
authors.initials: D
authors.lastname: Eliezer
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Hilal A
authors.initials: HA
authors.lastname: Lashuel
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism*; D003402:Creatine Kinase / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D016631:Lewy Bodies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020961:Lewy Body Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019578:Multiple System Atrophy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation; D011108:Polymers / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012694:Serine / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D011108:Polymers; D020033:Protein Isoforms; D051844:alpha-Synuclein; D012694:Serine; D003402:Creatine Kinase