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Multiple molecular pathways stimulating macroautophagy protect from alpha-synuclein-induced toxicity in human neurons.
Neuropharmacol. 149, 13-26 (2019)
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Chaperone-mediated Autophagy; Parkinsons-disease; Cell-death; Inhibition; Neurodegeneration; Monophosphatase; Carbamazepine; Degradation; Clearance; Apoptosis
Institute(s) Institute of Developmental Genetics (IDG)