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Content archived on 2024-05-27

Effects of posttranslational modifications of alpha-synuclein on dopaminergic neurodegeneration in a novel viral vector mediated in vivo model of Parkinson’s disease

Objective

One of the major pathological hallmarks of Parkinson´s disease (PD) is the progressive loss of specific dopaminergic projection neurons, especially those located in the substantia nigra pars compacta. The neurodegeneration is accompanied by the presence of cytoplasmic inclusions called Lewy bodies, which invariably contain the α-synuclein (α-syn) protein as a major component. Aggregation of α-syn in the brains of PD patients has attracted much attention also because point mutations in the α-syn gene were found to cause rare dominantly inherited form of PD. Although the precise mechanism of the selective vulnerability of dopaminergic neurons in the midbrain remains unknown, there is increasing evidence that multiple pathogenic factors including impaired handling of cytoplasmic dopamine (DA), elevated levels of reactive oxygen species (ROS) and abnormal phosphorylation of α-syn could cause selective death of these cells via the accumulation of soluble neurotoxic α-syn species. Building on the know how and expertise of the host lab I propose to study 1) the pathogenic interaction of DA/α-syn by genetically increasing cytoplasmic DA levels in the viral vector mediated α-syn overexpression model, which I propose would result in a more pronounced neurodegeneration; 2) the role of ROS by upregulation of the enzyme methionine sulfoxide reductase A (known to prevent oxidative damage by scavenging of ROS). I hypothesize that expression of this enzyme should result in protection of dopaminergic neurons in the α-syn overexpression model; and 3) the consequences of increased Ser 129 phosphorylation of α-syn by overexpressed polo like kinases, which should modify neurotoxicity in the viral vector mediated α-syn overexpression model. These 3 approaches could give important clues for understanding the mechanisms underlying the selective neurodegeneration in PD and thus lead to the development of novel therapeutic strategies in PD.

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Topic(s)

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Call for proposal

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FP7-PEOPLE-2009-IEF
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Funding Scheme

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MC-IEF - Intra-European Fellowships (IEF)

Coordinator

MAX IV Laboratory, Lund University
EU contribution
€ 179 669,40
Address
Paradisgatan 5c
22100 LUND
Sweden

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Region
Södra Sverige Sydsverige Skåne län
Activity type
Higher or Secondary Education Establishments
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Total cost

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