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Molecular Neurodegeneration

, 5:47

First Online: 04 November 2010Received: 16 August 2010Accepted: 04 November 2010

Abstract

Backgroundα-Synuclein aggregates in Lewy bodies and plays a central role in the pathogenesis of a group of neurodegenerative disorders, known as -Synucleinopathies-, including Parkinson-s disease. Parkin mutations result in loss of parkin E3-ubiquitin ligase activity and cause autosomal recessive early onset parkinsonism.

ResultsWe tested how these two genes interact by examining the effects of parkin on post-translational modification of α-Synuclein in gene transfer animal models, using a lentiviral gene delivery system into the striatum of 2-month old male Sprague Dawley rats.

Viral expression of wild type α-Synuclein caused accumulation of α-Synuclein and was associated with increased cell death and inflammation. α-Synuclein increased PLK2 levels and GSK-3β activity and increased the levels of phosphorylated α-Synuclein and Tau. Parkin co-expression reduced the levels of phosphorylated α-Synuclein and attenuated cell death and inflammation. Parkin reduced PLK2 levels and increased PP2A activation.

ConclusionsThese data suggest that parkin reduces α-Synuclein levels and alters the balance between phosphatase and kinase activities that affect the levels of phosphorylated α-Synuclein. These results indicate novel mechanisms for parkin protection against α-Synuclein-induced toxicity in PD.

AbbreviationsM.O.Imultiplicity of infection

PDParkinson-s disease

PP2Aphosphatase 2A

PLK2Polo-Like Kinase-2

P-SER 129α-Synuclein phosphorylated at serine 129

P-SER 87α-Synuclein phosphorylated at serine 87

SNsubstantia nigra

LBSLewy Bodies

LV-PARlentiviral parkin

LV-SYNLentiviral α-Synuclein

LV-LACZlentiviral LacZ.

Electronic supplementary materialThe online version of this article doi:10.1186-1750-1326-5-47 contains supplementary material, which is available to authorized users.

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Autor: Preeti J Khandelwal - Sonya B Dumanis - Li Rebekah Feng - Kathleen Maguire-Zeiss - GW Rebeck - Hilal A Lashuel - Charbel

Fuente: https://link.springer.com/







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