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Höllerhage, Matthias; Möbius, Claudia; Melms, Johannes; Chiu, Wei-Hua; Goebel, Joachim N.; Chakroun, Tasnim; Köglsperger, Thomas; Örtel, Wolfgang H.; Rösler, Thomas W.; Bickle, Marc; Höglinger, Günter U. (2017): Protective efficacy of phosphodiesterase-1 inhibition against alpha-synuclein toxicity revealed by compound screening in LUHMES cells. In: Scientific Reports, Vol. 7, 11469
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alpha-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 alpha-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 alpha-synuclein toxicity. Protection was mediated by an increase of cGMP and associated with the reduction of a specific alpha-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 alpha-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.