Abstract
Pathological aggregates of alpha-synuclein are the common hallmarks of synucleinopathies, including Parkinson's disease. There is currently no disease-modifying therapy approved for neurodegenerative synucleinopathies. The induction of macroautophagy by small compounds may be a strategy to reduce the cellular alpha-synuclein burden and to confer neuroprotection. Therefore, in the present study, we investigated a broad spectrum of druggable molecular signaling pathways reported to induce macroautophagy in human cells and compared their protective efficacy against alpha-synuclein-induced toxicity in cultured human postmitotic dopaminergic neurons. Several compounds affecting different pathways were able to activate macroautophagy. All compounds that activated autophagy also protected against alpha-synuclein-induced toxicity. The compounds with the lowest effective concentrations were PI-103, L-690,330, and NF 449, making them particularly interesting for further investigations, including in vivo models. Our findings demonstrate that activation of macroautophagy, as a neuroprotective approach in synucleinopathies, is accessible to pharmacotherapy. Moreover, pharmacological activation of macroautophagy via diverse signaling pathways is effective to protect human dopaminergic neurons against alpha-synuclein-induced toxicity.
| Dokumententyp: | Zeitschriftenartikel |
|---|---|
| Fakultät: | Medizin
Medizin > Munich Cluster for Systems Neurology (SyNergy) |
| Themengebiete: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit |
| ISSN: | 0028-3908 |
| Sprache: | Englisch |
| Dokumenten ID: | 81237 |
| Datum der Veröffentlichung auf Open Access LMU: | 15. Dez. 2021, 14:57 |
| Letzte Änderungen: | 06. Jun. 2024, 14:02 |
| DFG: | Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198 |
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