Parkinson-related parkin reduces α-Synuclein phosphorylation in a gene transfer model

Preeti J Khandelwal,Li Rebekah Feng,Hilal A Lashuel,Charbel Eh Moussa,Kathleen Maguire-Zeiss,Gw Rebeck,Sonya B Dumanis

doi:10.1186/1750-1326-5-47

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.

Highlights

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by death of dopaminergic neurons in the substantia nigra (SN) and accumulation of a-Synuclein in intracellular inclusions known as Lewy bodies (LBs) [1,2,3,4,5,6,7,8,9,10]
We further tested the levels of Polo-LikeKinase-2 (PLK2), which is known to phosphorylate a-Synuclein at Serine-129 and we found that PLK2 levels were significantly increased (54%, N = 4, P < 0.05) in a-Synuclein injected brains compared to LacZ or parkin levels (Figure 5B &5E)
Phosphorylation of a-Synuclein in PD and other Synucleinopathies may be mitigated by the effects of PP2A

Summary

Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by death of dopaminergic neurons in the substantia nigra (SN) and accumulation of a-Synuclein in intracellular inclusions known as Lewy bodies (LBs) [1,2,3,4,5,6,7,8,9,10]. P-Ser 129 was initially reported to accelerate the oligomerization and fibrillization of a-Synuclein [11,14,15], as well as accumulation and aggregation of a-Synuclein in animal models of Synucleinopathies [16,17]. Parkin deficiency in mice results in accumulation of non-ubiquitinated forms of a-Synuclein in the brain [22,23], and loss of function mutation results in degeneration of dopaminergic neurons in transgenic flies [27]. Native a-Synuclein does not appear to be a parkin substrate [28], several parkin over-expressing animal models display protection against a-Synuclein toxicity [25,26,29,30], suggesting a link between the two proteins

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