| Autor: |
Höllerhage, M., Moebius, C., Melms, J., Chiu, W.H., Goebel, J.N., Chakroun, T., Koeglsperger, T., Oertel, W.H., Rösler, T.W., Bickle, M., Höglinger, G.U. |
| Jazyk: |
němčina |
| Rok vydání: |
2017 |
| Předmět: |
|
| Zdroj: |
Sci. Rep. 7:11469 (2017) |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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