Multiple molecular pathways stimulating macroautophagy protect from alpha-synuclein-induced toxicity in human neurons

Abstract

&NA; 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. HighlightsmTOR‐dependent and mTOR‐independent ways to stimulate macroautophagy are effective in human dopaminergic neurons.Effective ways to stimulate macroautophagy in human dopaminergic neurons also protect from alpha‐synuclein‐induced toxicity.Inhibitors of P13K/mTOR (PI‐103), IMPase (L‐690,330), and Gs&agr;/FGFR3 (NF 449) were effective at the lowest concentrations.