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Elucidating the Role of Phosphorylation by Polo-like kinases in Modulating Alpha-Synuclein Aggregation and Toxicity in Parkinson's disease and Related Disorders

Objective

Increasing evidence suggest that alpha-synuclein (a-syn) phosphorylation plays an important role in the regulation of a-syn aggregation, Lewy Bodies (LBs) formation and neurotoxicity in Parkinson’s disease (PD) and related synucleopathies. However, the exact kinase(s) responsible for phosphorylating a-syn and the relationships between phosphorylation, a-syn fibrillogenesis, LB formation and cell death have not been fully elucidated. Preliminary data in our Laboratory have pointed out a Polo-Like Kinase family (Plks) as an interesting candidate for a-syn phosphorylation and modulating protein aggregation. To determine the relationship between the phosphorylation of a-syn by Plk family, protein aggregation and neurodegeneration, we plan to use an integrative approach combining in vitro and in vivo approaches. In the in vitro part, we seek to elucidate the role of phosphorylation by Plks in modulating a-syn aggregation in vitro and in primary cell culture. In the in vivo part, we plan to study the possible co-localization of Plks and phosphorylated and unphosphorylated a-syn in LBs inclusions in the brain of parkinsonians patients and animal models of PD. We also seek to evaluate the biochemical and functional consequences of co-delivering Plks and various modified forms of a-syn directly to the rodent brain. This proposal will give us the opportunity to better understand functional consequences of a-syn phosphorylation and mechanisms by which it contributes to neurotoxicity. That will allow us to identify new therapeutic targets of synucleopathies treatment.
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Coordinator

ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE

Address

Batiment Ce 3316 Station 1
1015 Lausanne

Switzerland

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 180 234,43

Administrative Contact

Lashuel Hilal (Prof.)

Project information

Grant agreement ID: 237688

Status

Closed project

  • Start date

    1 May 2009

  • End date

    30 April 2011

Funded under:

FP7-PEOPLE

  • Overall budget:

    € 180 234,43

  • EU contribution

    € 180 234,43

Coordinated by:

ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE

Switzerland