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Review: Multiple system atrophy: emerging targets for interventional therapies.

ABSTRACT: Multiple system atrophy (MSA) is a fatal orphan neurodegenerative disorder that manifests with rapidly progressive autonomic and motor dysfunction. The disease is characterized by the accumulation of ?-synuclein fibrils in oligodendrocytes that form glial cytoplasmic inclusions, a neuropathological hallmark and central player in the pathogenesis of MSA. Here, we summarize the current knowledge on the etiopathogenesis and neuropathology of MSA. We discuss the role of ?-synuclein pathology, microglial activation, oligodendroglial dysfunction and putative cell death mechanisms as candidate therapeutic targets in MSA.

SUBMITTER: Stefanova N

PROVIDER: S-EPMC4788141 | biostudies-other | 2016 Feb

REPOSITORIES: biostudies-other

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Review: Multiple system atrophy: emerging targets for interventional therapies.

Stefanova N N Wenning G K GK

Neuropathology and applied neurobiology 20160201 1

Multiple system atrophy (MSA) is a fatal orphan neurodegenerative disorder that manifests with rapidly progressive autonomic and motor dysfunction. The disease is characterized by the accumulation of α-synuclein fibrils in oligodendrocytes that form glial cytoplasmic inclusions, a neuropathological hallmark and central player in the pathogenesis of MSA. Here, we summarize the current knowledge on the etiopathogenesis and neuropathology of MSA. We discuss the role of α-synuclein pathology, microg ...[more]

PMID: 26785838

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Project description:Multiple system atrophy (MSA) is a rare atypical parkinsonian disorder characterized by a rapidly progressing clinical course and at present without any efficient therapy. Neuropathologically, myelin loss and neurodegeneration are associated with ?-synuclein accumulation in oligodendrocytes, but underlying pathomechanisms are poorly understood. Here, we analyzed the impact of oligodendrocytic ?-synuclein on the formation of myelin sheaths to define a potential interventional target for MSA. Post-mortem analyses of MSA patients and controls were performed to quantify myelin and oligodendrocyte numbers. As pre-clinical models, we used transgenic MSA mice, a myelinating stem cell-derived oligodendrocyte-neuron co-culture, and primary oligodendrocytes to determine functional consequences of oligodendrocytic ?-synuclein overexpression on myelination. We detected myelin loss accompanied by preserved or even increased numbers of oligodendrocytes in post-mortem MSA brains or transgenic mouse forebrains, respectively, indicating an oligodendrocytic dysfunction in myelin formation. Corroborating this observation, overexpression of ?-synuclein in primary and stem cell-derived oligodendrocytes severely impaired myelin formation, defining a novel ?-synuclein-linked pathomechanism in MSA. We used the pro-myelinating activity of the muscarinic acetylcholine receptor antagonist benztropine to analyze the reversibility of the myelination deficit. Transcriptome profiling of primary pre-myelinating oligodendrocytes demonstrated that benztropine readjusts myelination-related processes such as cholesterol and membrane biogenesis, being compromised by oligodendrocytic ?-synuclein. Additionally, benztropine restored the ?-synuclein-induced myelination deficit of stem cell-derived oligodendrocytes. Strikingly, benztropine also ameliorated the myelin deficit in transgenic MSA mice, resulting in a prevention of neuronal cell loss. In conclusion, this study defines the ?-synuclein-induced myelination deficit as a novel and crucial pathomechanism in MSA. Importantly, the reversible nature of this oligodendrocytic dysfunction opens a novel avenue for an intervention in MSA.

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Review: Multiple system atrophy: emerging targets for interventional therapies.

Publications

Review: Multiple system atrophy: emerging targets for interventional therapies.

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