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

Phytomedicine : international journal of phytotherapy and phytopharmacology 2025

["Liu G", "Zuo W", "Zhang Z", "Lv W", "Xu T", "Ma T", "Hou W", "Geng A", "Zhang Y"]

Abstract

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.

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