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  Translocator protein ligand protects against neurodegeneration in the MPTP mouse model of Parkinsonism.

Gong, J., Szego, E. M., Leonov, A., Benito, E., Becker, S., Fischer, A., et al. (2019). Translocator protein ligand protects against neurodegeneration in the MPTP mouse model of Parkinsonism. Journal of Neuroscience, (in press). doi:10.1523/JNEUROSCI.2070-18.2019.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-0F51-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-0F54-F
Genre: Journal Article

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Gong, J., Author
Szego, E. M., Author
Leonov, A.1, Author              
Benito, E., Author
Becker, S.1, Author              
Fischer, A., Author
Zweckstetter, M.2, Author              
Outeiro, T., Author
Schneider, A., Author
Affiliations:
1Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              
2Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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 Abstract: Parkinson's disease (PD) is the second most common neurodegenerative disease, after Alzheimer's disease. PD is a movement disorder with characteristic motor features that arise due to the loss of dopaminergic neurons from the substantia nigra. Although symptomatic treatment by the dopamine precursor levodopa and dopamine agonists can improve motor symptoms, no disease-modifying therapy exists yet. Here, we show that Emapunil (AC-5216, XBD-173), a synthetic ligand of the translocator protein 18 (TSPO), ameliorates degeneration of dopaminergic neurons, preserves striatal dopamine metabolism and prevents motor dysfunction in female mice treated with the 1-methyl-4-phenyl-1,-2,-3,-6-tetrahydropyridine (MPTP), as a model of parkinsonism. We found that Emapunil modulates the inositol requiring kinase 1 α (IRE α)/-X-box binding protein 1 (XBP1) unfolded protein response pathway and induces a shift from pro- towards anti-inflammatory microglia activation. Previously, Emapunil was shown to cross the blood brain barrier and to be safe and well-tolerated in a phase II clinical trial. Therefore, our data suggest that Emapunil may be a promising approach in the treatment of Parkinson's disease.Significance statementOur study reveals a beneficial effect of Emapunil on dopaminergic neuron survival, dopamine metabolism and motor phenotype in the MPTP mouse model of parkinsonism. In addition, our work uncovers molecular networks which mediate neuroprotective effects of Emapunil, including microglial activation state and unfolded protein response pathways. These findings not only contribute to our understanding of biological mechanisms of TSPO function but also indicate that TSPO may be a promising therapeutic target. We thus propose to further validate Emapunil in other Parkinson's disease mouse models and subsequently in clinical trials to treat Parkinson's disease.

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Language(s): eng - English
 Dates: 2019-02-22
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1523/JNEUROSCI.2070-18.2019
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Title: Journal of Neuroscience
Source Genre: Journal
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Pages: - Volume / Issue: - Sequence Number: (in press) Start / End Page: - Identifier: -