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

Katerina E. Paleologou, Abid Oueslati, Gideon Shakked, Carla C. Rospigliosi, Hai Young Kim, Gonzalo R. Lamberto, Claudio O. Fernandez, Adrian Schmid, Fariba Chegini, Wei Ping Gai, Diego Chiappe, Marc Moniatte, Bernard L. Schneider, Patrick Aebischer, David Eliezer, Markus Zweckstetter, Eliezer Masliah, Hilal A. Lashuel

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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 normalcontrols. In brainhomogenatesfromdiseasedhumanbrainsandTGanimals, the majority ofS87-P α-synwasdetected in themembrane fractions.Abattery of biophysical methods were used to dissect the effect of S87 phosphorylation on the structure, aggregation, andmembranebinding 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.

Original languageEnglish
Pages (from-to)3184-3198
Number of pages15
JournalJournal of Neuroscience
Volume30
Issue number9
DOIs
Publication statusPublished - 3 Mar 2010
Externally publishedYes

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Synucleins
Phosphorylation
Membranes
Multiple System Atrophy
Alzheimer Disease
Lewy Bodies
Lewy Body Disease
Brain Diseases
Parkinson Disease
Antibodies
Brain

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Paleologou, K. E., Oueslati, A., Shakked, G., Rospigliosi, C. C., Kim, H. Y., Lamberto, G. R., ... Lashuel, H. A. (2010). Phosphorylation at S87 is enhanced in synucleinopathies, inhibits α-synuclein oligomerization, and influences synuclein-membrane interactions. Journal of Neuroscience, 30(9), 3184-3198. https://doi.org/10.1523/JNEUROSCI.5922-09.2010

Phosphorylation at S87 is enhanced in synucleinopathies, inhibits α-synuclein oligomerization, and influences synuclein-membrane interactions. / Paleologou, Katerina E.; Oueslati, Abid; Shakked, Gideon; Rospigliosi, Carla C.; Kim, Hai Young; Lamberto, Gonzalo R.; Fernandez, Claudio O.; Schmid, Adrian; Chegini, Fariba; Gai, Wei Ping; Chiappe, Diego; Moniatte, Marc; Schneider, Bernard L.; Aebischer, Patrick; Eliezer, David; Zweckstetter, Markus; Masliah, Eliezer; Lashuel, Hilal A.

In: Journal of Neuroscience, Vol. 30, No. 9, 03.03.2010, p. 3184-3198.

Research output: Contribution to journalArticle

Paleologou, KE, Oueslati, A, Shakked, G, Rospigliosi, CC, Kim, HY, Lamberto, GR, Fernandez, CO, Schmid, A, Chegini, F, Gai, WP, Chiappe, D, Moniatte, M, Schneider, BL, Aebischer, P, Eliezer, D, Zweckstetter, M, Masliah, E & Lashuel, HA 2010, 'Phosphorylation at S87 is enhanced in synucleinopathies, inhibits α-synuclein oligomerization, and influences synuclein-membrane interactions', Journal of Neuroscience, vol. 30, no. 9, pp. 3184-3198. https://doi.org/10.1523/JNEUROSCI.5922-09.2010
Paleologou, Katerina E. ; Oueslati, Abid ; Shakked, Gideon ; Rospigliosi, Carla C. ; Kim, Hai Young ; Lamberto, Gonzalo R. ; Fernandez, Claudio O. ; Schmid, Adrian ; Chegini, Fariba ; Gai, Wei Ping ; Chiappe, Diego ; Moniatte, Marc ; Schneider, Bernard L. ; Aebischer, Patrick ; Eliezer, David ; Zweckstetter, Markus ; Masliah, Eliezer ; Lashuel, Hilal A. / Phosphorylation at S87 is enhanced in synucleinopathies, inhibits α-synuclein oligomerization, and influences synuclein-membrane interactions. In: Journal of Neuroscience. 2010 ; Vol. 30, No. 9. pp. 3184-3198.
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AU - Paleologou, Katerina E.

AU - Oueslati, Abid

AU - Shakked, Gideon

AU - Rospigliosi, Carla C.

AU - Kim, Hai Young

AU - Lamberto, Gonzalo R.

AU - Fernandez, Claudio O.

AU - Schmid, Adrian

AU - Chegini, Fariba

AU - Gai, Wei Ping

AU - Chiappe, Diego

AU - Moniatte, Marc

AU - Schneider, Bernard L.

AU - Aebischer, Patrick

AU - Eliezer, David

AU - Zweckstetter, Markus

AU - Masliah, Eliezer

AU - Lashuel, Hilal A.

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N2 - 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 normalcontrols. In brainhomogenatesfromdiseasedhumanbrainsandTGanimals, the majority ofS87-P α-synwasdetected in themembrane fractions.Abattery of biophysical methods were used to dissect the effect of S87 phosphorylation on the structure, aggregation, andmembranebinding 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.

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