title: Enhancing lysosomal biogenesis and autophagic flux by activating the transcription factor EB protects against cadmium-induced neurotoxicity.
abstract: Cadmium (Cd), a highly ubiquitous heavy metal, is a well-known inducer of neurotoxicity. However, the mechanism underlying cadmium-induced neurotoxicity remains unclear. In this study, we found that Cd inhibits autophagosome-lysosome fusion and impairs lysosomal function by reducing the levels of lysosomal-associated membrane proteins, inhibiting lysosomal proteolysis and altering lysosomal pH, contributing to defects in autophagic clearance and subsequently leading to nerve cell death. In addition, Cd decreases transcription factor EB (TFEB) expression at both the mRNA and protein levels. Furthermore, Cd induces the nuclear translocation of TFEB and TFEB target-gene expression, associated with compromised lysosomal function or a compensatory effect after the impairment of the autophagic flux. Notably, restoration of the levels of lysosomal-associated membrane protein, lysosomal proteolysis, lysosomal pH and autophagic flux through Tfeb overexpression protects against Cd-induced neurotoxicity, and this protective effect is incompletely dependent on TFEB nuclear translocation. Moreover, gene transfer of the master autophagy regulator TFEB results in the clearance of toxic proteins and the correction of Cd-induced neurotoxicity in vivo. Our study is the first to demonstrate that Cd disrupts lysosomal function and autophagic flux and manipulation of TFEB signalling may be a therapeutic approach for antagonizing Cd-induced neurotoxicity.
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Huifeng
authors.initials: H
authors.lastname: Pi
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Tian
authors.affiliation: Brain Research Center, Third Military Medical University, Chongqing 400038, People's Republic of China.|Department of Neurology, Army General Hospital in Lanzhou, Lanzhou 730000, People's Republic of China.
authors.forename: Zhiqi
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.|Department of Occupational and Environmental Health, School of Medicine, Guangxi University, Nanning 530004, People's Republic of China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D002104:Cadmium / Q000633:toxicity*; D002402:Cathepsin D / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D006863:Hydrogen-Ion Concentration; D051907:Lysosomal Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001678:Organelle Biogenesis; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D021381:Protein Transport; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002104:Cadmium; D002402:Cathepsin D; D051907:Lysosomal Membrane Proteins; D008869:Microtubule-Associated Proteins; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1; C480860:Map1lc3b protein, mouse; C484068:Tcfeb protein, mouse; C533923:Ctsd protein, mouse