FAS-Dependent Cell Death in α-Synuclein Transgenic Oligodendrocyte Models of Multiple System Atrophy

Christine L Kragh,Hanne D Hansen,Christiane Richter-Landsberg,Gwenaëlle Fillon,Poul H Jensen,Glenda M Halliday,Philipp J Kahle,Christian Haass,Catherine Lubetzki,Manuela Neumann,Bernard Zalc,Amanda Gysbers,Wei-Ping Gai

doi:10.1371/journal.pone.0055243

Abstract

Multiple system atrophy is a parkinsonian neurodegenerative disorder. It is cytopathologically characterized by accumulation of the protein p25α in cell bodies of oligodendrocytes followed by accumulation of aggregated α-synuclein in so-called glial cytoplasmic inclusions. p25α is a stimulator of α-synuclein aggregation, and coexpression of α-synuclein and p25α in the oligodendroglial OLN-t40-AS cell line causes α-synuclein aggregate-dependent toxicity. In this study, we investigated whether the FAS system is involved in α-synuclein aggregate dependent degeneration in oligodendrocytes and may play a role in multiple system atrophy. Using rat oligodendroglial OLN-t40-AS cells we demonstrate that the cytotoxicity caused by coexpressing α-synuclein and p25α relies on stimulation of the death domain receptor FAS and caspase-8 activation. Using primary oligodendrocytes derived from PLP-α-synuclein transgenic mice we demonstrate that they exist in a sensitized state expressing pro-apoptotic FAS receptor, which makes them sensitive to FAS ligand-mediated apoptosis. Immunoblot analysis shows an increase in FAS in brain extracts from multiple system atrophy cases. Immunohistochemical analysis demonstrated enhanced FAS expression in multiple system atrophy brains notably in oligodendrocytes harboring the earliest stages of glial cytoplasmic inclusion formation. Oligodendroglial FAS expression is an early hallmark of oligodendroglial pathology in multiple system atrophy that mechanistically may be coupled to α-synuclein dependent degeneration and thus represent a potential target for protective intervention.

Highlights

Multiple system atrophy (MSA) is a sporadic and progressive neurodegenerative disease that presents with motor abnormalities like akinesia, rigidity and postural instability
Unlike the other a-synucleinopathies of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), which are characterized by neuronal aggregates of a-synuclein (a-syn), MSA is neuropathologically characterized by glial cytoplasmic inclusions (GCIs) containing aggregated a-syn in oligodendrocytes [1,2,3]
Double labeling immunofluorescence demonstrated that FAS and a-syn rarely colocalized within GCIs (Fig. 4I, L) but FAS was present in some oligodendrocytes harboring a-syn positive GCIs

Summary

Introduction

Multiple system atrophy (MSA) is a sporadic and progressive neurodegenerative disease that presents with motor abnormalities like akinesia, rigidity and postural instability. The pathogenic potential of a-syn in oligodendrocytes has been demonstrated in transgenic (tg) mice overexpressing human asyn under the control of oligodendrocyte-specific promoters [CNPase, MBP and PLP] [4,5,6]. These tg mice develop a-syn accumulations in oligodendrocytes and exhibit oligodendroglial and neuronal pathology or increased sensitivity to toxins [7,8]. In addition to oligodendrocytic myelin loss and a-syn accumulation, MSA patients display considerable neuronal loss accompanied by astrogliosis and microgliosis [10,11] This is recapitulated in tg mouse models overexpressing human a-syn in oligodendrocytes [5,6].

Materials and Methods

Findings

Discussion