α-synuclein aggregation and Ser-129 phosphorylation-dependent cell death in oligodendroglial cells

Christine L. Kragh, Louise B. Lund, Fabia Febbraro, Hansen D. Hansen, Gai Wei-Ping, Omar Ali El-Agnaf, Christiane Richter-Landsberg, Poul Henning Jensen

Research output: Contribution to journalArticle

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Abstract

Multiple system atrophy is a neurodegenerative disorder characterized by accumulation of aggregated Ser-129-phosphorylated α-synuclein in oligodendrocytes. p25α is an oligodendroglial protein that potently stimulates α-synuclein aggregation in vitro. To model multiple system atrophy, we coexpressed human p25α and α-synuclein in the rat oligodendroglial cell line OLN-93 and observed a cellular response characterized by a fast retraction of microtubules from the cellular processes to the perinuclear region followed by a protracted development of apoptosis. This response was dependent on phosphorylation at Ser-129 in α-synuclein as demonstrated by site-directed mutagenesis. Treatment of the cells with the kinase inhibitor 2-dimethylamino-4,5,6,7-tetrabromo-1H benzimidazole that targets kinases like casein kinase 2, and polo-like kinases abrogated the toxicity. The polo-like kinase inhibitor BI 2536 caused apoptosis in the model. Ser-129 phosphorylation was linked to the formation of phosphorylated oligomers detectable by immunoblotting, and their formation was inhibited by 2-dimethylamino-4,5,6,7-tetrabromo-1H benzimidazole. The process of microtubule retraction was also dependent on aggregation as demonstrated by the protective effect of treating the cells with the specific peptide inhibitor of α-synuclein aggregation ASI1D and the non-selective inhibitors Congo Red and baicalein. The fast microtubule retraction was followed by the development of the apoptotic markers: activated caspase-3, phosphatidylserine externalization, nuclear condensation, and fragmentation. These markers could all be blocked by the inhibitors of phosphorylation, aggregation, and caspase-3. Hence, the model predicts that both Ser-129 phosphorylation and aggregation control the toxic α-syn pathway in oligodendroglial cells and may represent therapeutic intervention points in multiple system atrophy.

Original languageEnglish
Pages (from-to)10211-10222
Number of pages12
JournalJournal of Biological Chemistry
Volume284
Issue number15
DOIs
Publication statusPublished - 10 Apr 2009
Externally publishedYes

Fingerprint

Synucleins
Phosphorylation
Cell death
Cell Death
Multiple System Atrophy
Agglomeration
Phosphotransferases
Microtubules
Caspase 3
Cells
Apoptosis
Casein Kinase II
Congo Red
Mutagenesis
Poisons
Phosphatidylserines
Oligodendroglia
Site-Directed Mutagenesis
Oligomers
Immunoblotting

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

α-synuclein aggregation and Ser-129 phosphorylation-dependent cell death in oligodendroglial cells. / Kragh, Christine L.; Lund, Louise B.; Febbraro, Fabia; Hansen, Hansen D.; Wei-Ping, Gai; Ali El-Agnaf, Omar; Richter-Landsberg, Christiane; Jensen, Poul Henning.

In: Journal of Biological Chemistry, Vol. 284, No. 15, 10.04.2009, p. 10211-10222.

Research output: Contribution to journalArticle

Kragh, CL, Lund, LB, Febbraro, F, Hansen, HD, Wei-Ping, G, Ali El-Agnaf, O, Richter-Landsberg, C & Jensen, PH 2009, 'α-synuclein aggregation and Ser-129 phosphorylation-dependent cell death in oligodendroglial cells', Journal of Biological Chemistry, vol. 284, no. 15, pp. 10211-10222. https://doi.org/10.1074/jbc.M809671200
Kragh, Christine L. ; Lund, Louise B. ; Febbraro, Fabia ; Hansen, Hansen D. ; Wei-Ping, Gai ; Ali El-Agnaf, Omar ; Richter-Landsberg, Christiane ; Jensen, Poul Henning. / α-synuclein aggregation and Ser-129 phosphorylation-dependent cell death in oligodendroglial cells. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 15. pp. 10211-10222.
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