The role of GSK3β signaling mediated lysosomal biosynthesis dysregulation in fluoride-induced neurological impairment.

Abstract

Neurological dysfunction induced by fluoride is still one of major concern worldwide, yet the underlying mechanisms remain elusive. To explore whether fluoride disrupts lysosomal biosynthesis via the GSK3β signaling, leading to neurological damage, both in vivo rat models and in vitro PC12 cell models were conducted. Subsequent findings revealed reduced spatial learning and memory abilities, decreased hippocampal neurons, and disrupted neuronal arrangement in NaF-treated rats. In vitro, PC12 cells exhibited decreased cell viability and increased apoptosis rates after NaF treatment for 24 h. Moreover, immunofluorescence assays demonstrated that there is a reduction in the number of mature lysosomes and an increase in immature lysosomes in NaF-treated PC12 cells, evident by decreased co-localization of LAMP1 with Arl8b, and increased co-localization of LAMP1 with Rab7. Furthermore, both in vivo and in vitro, the protein expression of cleaved caspase-3 was upregulated, whereas the protein expressions of TFEB and CTSB were downregulated. The GSK3β signaling activation was detected, and this was confirmed by silencing GSK3β with siRNA in vitro. Collectively, these results indicate that NaF can impair lysosomal biosynthesis via GSK3β signaling, promoting neuronal apoptosis, and consequently impairing neurological function in rats.