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Sci Rep. 2017 Sep 13;7(1):11469. doi: 10.1038/s41598-017-11664-5.

Protective efficacy of phosphodiesterase-1 inhibition against alpha-synuclein toxicity revealed by compound screening in LUHMES cells.

Author information

1
Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), D-81377, Munich, Germany.
2
Department of Neurology, Technical University of Munich, D-81675, Munich, Germany.
3
HT-Technology Development Studio, Max Planck Institute of Molecular Cell Biology and Genetics, D-01307, Dresden, Germany.
4
Department of Neurology, University of Marburg, D-35043, Marburg, Germany.
5
Munich Cluster for Systems Neurology (SyNergy), D-81337, Munich, Germany.
6
Department of Neurology, Ludwig Maximilian University of Munich, D-81377, Munich, Germany.
7
Institute of Neurogenomics, Helmholtz Center Munich, D-85764, Neuherberg, Germany.
8
Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), D-81377, Munich, Germany. guenter.hoeglinger@dzne.de.
9
Department of Neurology, Technical University of Munich, D-81675, Munich, Germany. guenter.hoeglinger@dzne.de.
10
Munich Cluster for Systems Neurology (SyNergy), D-81337, Munich, Germany. guenter.hoeglinger@dzne.de.

Abstract

α-synuclein-induced neurotoxicity is a core pathogenic event in neurodegenerative synucleinopathies such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. There is currently no disease-modifying therapy available for these diseases. We screened 1,600 FDA-approved drugs for their efficacy to protect LUHMES cells from degeneration induced by wild-type α-synuclein and identified dipyridamole, a non-selective phosphodiesterase inhibitor, as top hit. Systematic analysis of other phosphodiesterase inhibitors identified a specific phosphodiesterase 1 inhibitor as most potent to rescue from α-synuclein toxicity. Protection was mediated by an increase of cGMP and associated with the reduction of a specific α-synuclein oligomeric species. RNA interference experiments confirmed PDE1A and to a smaller extent PDE1C as molecular targets accounting for the protective efficacy. PDE1 inhibition also rescued dopaminergic neurons from wild-type α-synuclein induced degeneration in the substantia nigra of mice. In conclusion, this work identifies inhibition of PDE1A in particular as promising target for neuroprotective treatment of synucleinopathies.

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