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.
Highlights
Parkinson’s disease (PD) is the most frequent neurodegenerative movement disorder
A resource-sparing alternative approach is the screening of drugs already approved for use in humans, to identify previously unrecognized neuroprotective effects, which might qualify them for being repositioned into new indications
A systematic analysis of specific inhibitors of PDE isoenzymes identified potent neuroprotective properties of the PDE1 inhibitor vinpocetine, which was not part of the screening library. siRNA-mediated silencing of PDE1A, and with inferior efficacy silencing of PDE1C, reproduced the protective effects of the pharmacological inhibitors, validating these as molecular targets
Summary
Parkinson’s disease (PD) is the most frequent neurodegenerative movement disorder. Its clinical core features are bradykinesia, rigidity, and tremor[1]. It was previously shown that mouse α-Syn interacts with human α-Syn and affects aggregation[16] This demonstrates that the exact nature of the pathogenic α-Syn species and the mechanisms leading to cell death are not yet fully understood. Despite the approaches described above, there is currently no known therapy with proven efficacy to slow or halt their progression, since all clinical trials with potentially neuroprotective interventions failed so far to show any disease modifying effects in synucleinopathies (e.g. refs 23 and 24). To identify novel therapies against α-Syn-induced neurodegeneration, we have developed a model in which moderate overexpression of wild-type α-Syn with adenoviral vectors in postmitotic dopaminergic Lund human mesencephalic (LUHMES) neurons in vitro leads to ~50% cell death within six days[18]. We miniaturized and automatized this model to perform a screening of 1,600 FDA-approved drugs
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