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Novel animal model defines genetic contributions for neuron-to-neuron transfer of ?-synuclein.

ABSTRACT: Cell-to-cell spreading of misfolded ?-synuclein (?-syn) is suggested to contribute to the progression of neuropathology in Parkinson's disease (PD). Compelling evidence supports the hypothesis that misfolded ?-syn transmits from neuron-to-neuron and seeds aggregation of the protein in the recipient cells. Furthermore, ?-syn frequently appears to propagate in the brains of PD patients following a stereotypic pattern consistent with progressive spreading along anatomical pathways. We have generated a C. elegans model that mirrors this progression and allows us to monitor ?-syn neuron-to-neuron transmission in a live animal over its lifespan. We found that modulation of autophagy or exo/endocytosis, affects ?-syn transfer. Furthermore, we demonstrate that silencing C. elegans orthologs of PD-related genes also increases the accumulation of ?-syn. This novel worm model is ideal for screening molecules and genes to identify those that modulate prion-like spreading of ?-syn in order to target novel strategies for disease modification in PD and other synucleinopathies.

SUBMITTER: Tyson T

PROVIDER: S-EPMC5548897 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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Novel animal model defines genetic contributions for neuron-to-neuron transfer of α-synuclein.

Tyson Trevor T Senchuk Megan M Cooper Jason F JF George Sonia S Van Raamsdonk Jeremy M JM Brundin Patrik P

Scientific reports 20170808 1

Cell-to-cell spreading of misfolded α-synuclein (α-syn) is suggested to contribute to the progression of neuropathology in Parkinson's disease (PD). Compelling evidence supports the hypothesis that misfolded α-syn transmits from neuron-to-neuron and seeds aggregation of the protein in the recipient cells. Furthermore, α-syn frequently appears to propagate in the brains of PD patients following a stereotypic pattern consistent with progressive spreading along anatomical pathways. We have generate ...[more]

PMID: 28790319

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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.

Dataset Information

Novel animal model defines genetic contributions for neuron-to-neuron transfer of ?-synuclein.

Publications

Novel animal model defines genetic contributions for neuron-to-neuron transfer of α-synuclein.

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