2024: mTORC1/TFEB axis - fluoride neurotoxicity - Resveratrol

[pfpcnews]

NOTE:
1) Fluoride inhibits TFEB - T3 activates TFEB. (see: Tseng et al., 2023)
2) mTOR signalling requires Gq/11 (Li et al., 2016) [see: ERK1/2]


Tang H, Hou H, Song L, Tian Z, Liu W, Xia T, Wang A - "The role of mTORC1/TFEB axis mediated lysosomal biogenesis and autophagy impairment in fluoride neurotoxicity and the intervention effects of resveratrol" J Hazard Mater 467:133634 (2024). doi: 10.1016/j.jhazmat.2024.133634
https://pubmed.ncbi.nlm.nih.gov/38335616/

Abstract

Elevated exposures to fluoride have been linked to neurological diseases. Identifying mechanisms of fluoride neurotoxicity and finding ways for prevention and treatment of epidemic fluorosis are important issues of public health. In this study, fluoride inhibited TFEB nuclear translocation by activating p-mTORC1/p-p70S6K, thus inhibiting lysosomal biogenesis, leading to dysfunctional lysosome accumulation, which further negatively affected autophagosome and lysosome fusion, thus impairing autophagy degradation, evidenced by the blocked conversion of LC3II to LC3I, and the increased p62 levels. Interestingly, RSV alleviated rats' cognition by improving fluoride-induced nerve damage and promoted lysosomal biogenesis demonstrated by the increased nucleus translocation of TFEB via inhibiting p-mTORC1 and p-p70S6K, the decreased expression of LC3II and p62. Collectively, we clarified the correlation between fluoride neurotoxicity and mTORC1/TFEB-mediated lysosomal biogenesis and autophagy. Meanwhile, RSV appeared to be a promising drug for the prevention and treatment of epidemic fluorosis.


Tseng YH, Chang CC, Lin KH - "Thyroid hormone upregulates LAMP2 expression and lysosome activity" Biochem Biophys Res Commun 662:66-75 (2023). doi: 10.1016/j.bbrc.2023.04.061
"Our findings showed that T3 activates rapid lysosomal turnover and expression of numerous lysosomal genes, including TFEB, LAMP2, ARSB, GBA, PSAP, ATP6V0B, ATP6V0D1, ATP6V1E1, CTSB, CTSH, CTSL, and CTSS, in a thyroid hormone receptor-dependent manner."

Li S, Yang C, Zhang L, Gao X, Wang X, Liu W, Wang Y, Jiang S, Wong YH, Zhang Y, Liu K - "Promoting axon regeneration in the adult CNS by modulation of the melanopsin/GPCR signaling" Proc Natl Acad Sci U S A 113(7):1937-42 (2016). doi: 10.1073/pnas.1523645113
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763730/
"Both the axon regeneration and mTOR activity that were enhanced by melanopsin required light stimulation and Gq/11 signaling. Specifically, activating Gq in RGCs elevated mTOR activation and promoted axonal regeneration."