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

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.

• Authors: Matthias Höllerhage, Claudia Moebius, Johannes Melms, Wei-Hua Chiu, Joachim N Goebel, Tasnim Chakroun, Thomas Koeglsperger, Wolfgang H Oertel, Thomas W Rösler, Marc Bickle, Günter U Höglinger
• Journal: Scientific reports (Sci Rep) Vol. 7 Issue 1 Pg. 11469 (09 13 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28904388 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Neuroprotective Agents
• Vinca Alkaloids
• alpha-Synuclein
• vinpocetine
• Dipyridamole
• Phosphodiesterase I

Topics

• Animals
• Cell Line
• Dipyridamole (pharmacology)
• Drug Discovery
• Drug Evaluation, Preclinical
• Enzyme Inhibitors (pharmacology)
• High-Throughput Screening Assays
• Humans
• Mice
• Neurons (drug effects, metabolism)
• Neuroprotective Agents (pharmacology)
• Phosphodiesterase I (antagonists & inhibitors)
• Protein Aggregation, Pathological (drug therapy, metabolism)
• Vinca Alkaloids (pharmacology)
• alpha-Synuclein (antagonists & inhibitors, metabolism)