Nucleolin inhibits α-synuclein to attenuate aconitine's neurotoxicity.

BACKGROUND

Aconitine (AC), a toxic alkaloid derived from Aconitum species, presents a significant risk of neurotoxicity with global poisoning reports.

PURPOSE: This study aimed to reveal the mechanism underlying the neurotoxicity of AC.

METHODS

The toxicity of AC was evaluated by behavioral tests, histological examinations, western blot (WB) and immunofluorescence. We studied its potential mechanism through transcriptome, proteomics, nascent transcripts and immunoprecipitation/mass spectrometry (IP/MS).

RESULTS

AC caused motor dysfunction and anxiety-like behaviors. And the peak of pyroptosis occurred at 8 h, accompanied by abnormal neurotransmitter-related metabolite expressions in brain tissue, ultrastructural damage and morphological changes in neurons. Importantly, transcriptomic and proteomic analyses indicate the elevation of α-synuclein (α-syn) level and the activation of the PI3K/Akt/mTOR pathway are key drivers of AC neurotoxicity. IP/MS further elucidated that nucleolin (Ncl) is essential for clearing p-α-syn (Ser129). The nascent transcript discovered that the peaks of nascent mRNA of Snca and Ncl appeared at 8 h after AC exposure. Meanwhile, we verified that AC activates the PI3K/Akt/mTOR pathway. Moreover, the hypothesis that Ncl is involved in reducing neurotoxicity by antagonizing AC - induced elevation of α-syn has been further verified in WB and motor behavior studies.

CONCLUSION

Our work reveals that the neurotoxicity induced by AC is attributed to the abnormal elevation of α-syn, and nucleolin has a clearance effect.