Overexpression of α-synuclein in oligodendrocytes does not increase susceptibility to focal striatal excitotoxicity.

Nadia Stefanova,Carlijn Borm,Gregor K. Wenning,Bastiaan Bloem,Deniz Kirik,Lisa Fellner,Daniela Kuzdas-Wood,Melanie Premstaller

doi:10.1186/s12868-015-0227-6

Abstract

BackgroundMultiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disease characterized by α-synuclein (α-syn) positive oligodendroglial cytoplasmic inclusions. The latter are associated with a neuronal multisystem neurodegeneration targeting central autonomic, olivopontocerebellar and striatonigral pathways, however the underlying mechanisms of neuronal cell death are poorly understood. Previous experiments have shown that oligodendroglial α-syn pathology increases the susceptibility to mitochondrial stress and proteasomal dysfunction leading to enhanced MSA-like neurodegeneration. Here we analyzed whether oligodendroglial α-syn overexpression in a transgenic mouse model of MSA synergistically interacts with focal neuronal excitotoxic damage generated by a striatal injection of quinolinic acid (QA) to affect the degree of striatal neuronal loss.ResultsQA injury led to comparable striatal neuronal loss and optical density of astro- and microgliosis in the striatum of transgenic and control mice. Respectively, no differences were identified in drug-induced rotation behavior or open field behavior between the groups.ConclusionsThe failure of oligodendroglial α-syn pathology to exacerbate striatal neuronal loss resulting from QA excitotoxicity contrasts with enhanced striatal neurodegeneration due to oxidative or proteolytic stress, suggesting that enhanced vulnerability to excitotoxicity does not occur in oligodendroglial α-synucleinopathy like MSA.

Highlights

Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disease characterized by α-synuclein (α-syn) positive oligodendroglial cytoplasmic inclusions
Oligodendroglial α‐syn accumulation does not enhance striatal excitotoxic lesions by focal quinolinic acid (QA) injection The loss of GABAergic medium-sized spiny neurons induced by 90 nmol QA injections into the left striatum was comparable in PLP-α-syn and control mice
The current results demonstrate that α-syn oligodendroglial pathology does not have a cumulative effect with the QA insult in the transgenic MSA model to affect either rearing or horizontal activity in an open field arena

Summary

Introduction

Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disease characterized by α-synuclein (α-syn) positive oligodendroglial cytoplasmic inclusions The latter are associated with a neuronal multi‐ system neurodegeneration targeting central autonomic, olivopontocerebellar and striatonigral pathways, the underlying mechanisms of neuronal cell death are poorly understood. Oligodendroglial α-syn overexpression in PLP-α-syn mice as well as MBP-α-syn mice resulted in increased 3-NP vulnerability associated with oxidative changes of α-syn pathology in oligodendrocytes that may partly mediate the enhanced neuronal vulnerability to systemic stress [12, 21, 22] Supporting this notion, systemic exposure to proteasome inhibition triggered wide-spread MSA-like neurodegeneration in transgenic PLP-α-syn mice but not in wild type controls highlighting the importance of aggravated oligodendroglial α-syn pathology through systemic proteolytic stress for increased neuronal vulnerability [23]

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