Long noncoding RNA FTX regulates lead-induced synaptic vesicle damage in a miR-20b-5p/SNAP25 dependent axis

Background: Lead exposure remains a significant global public health concern due to its widespread presence as an environmental pollutant and its persistent neurotoxic effects, particularly impairing cognitive function and synaptic integrity. Despite regulatory efforts, environmental lead exposure continues to pose a heavy societal burden, especially among vulnerable populations such as children. Recent research highlights the importance of non-coding RNAs, including lncRNAs and miRNAs, in the regulation of synaptic proteins. However, the molecular mechanisms underlying lead-induced synaptic dysfunction remain incompletely understood. Methods: Male C57BL/6 mice were exposed to 0, 100 ppm, or 300 ppm lead acetate in drinking water for 8 weeks. Behavioral assessments included the open field, novel object recognition, and Morris water maze tests. Hippocampal synaptic ultrastructure was examined by transmission electron microscopy (TEM). Expression of synaptic vesicle-associated proteins and regulatory RNAs (lncFTX, miR-20b-5p, SNAP25) was quantified by qRT-PCR and western blotting. In vitro, human hippocampal neuronal cells (HPPNCs) were exposed to lead acetate, and functional roles of lncFTX and miR-20b-5p were evaluated using transfection and dual-luciferase reporter assays. Results: Lead-exposed mice exhibited significant deficits in spatial learning and memory, with no effect on body weight or general locomotor activity. TEM revealed increased synaptic vesicle density and decreased vesicle diameter in the hippocampus of lead-exposed mice. qRT-PCR indicated downregulation of SNARE complex proteins (VAMP2, SNAP25, SYT1) and upregulation of SYN and SYP. In HPPNCs, lead acetate reduced cell viability and SNAP25 expression, while increasing SYN, SYP, and miR-20b-5p, and decreasing lncFTX. Dual-luciferase and transfection experiments demonstrated that lncFTX acts as a sponge for miR-20b-5p, which directly targets SNAP25. Knockdown of lncFTX or overexpression of miR-20b-5p reduced SNAP25 levels and neuronal viability, whereas inhibition of miR-20b-5p partially rescued these effects. Conclusions: Environmental lead exposure impairs learning and memory through synaptic vesicle dysregulation and coordinated downregulation of synaptic proteins, in part mediated by the lncFTX/miR-20b-5p/SNAP25 axis. These findings suggest that non-coding RNA networks contribute to lead-induced neurotoxicity, provide new molecular insights into environmental pollutant-induced neural impairment, and identify potential targets for intervention strategies.