title: Mercury is a direct and potent γ-secretase inhibitor affecting Notch processing and development in Drosophila.
abstract: Prenatal exposure to mercury causes neurodevelopmental disorders and neurological pathologies in infants, such as microcephaly and mental retardation. Despite critical importance, the molecular interactions leading to mercury toxicity are yet to be elucidated. We first used a cell-free assay to investigate mercury effects on purified γ-secretase activity. Next, we treated adult Drosophila melanogaster with mercury and collected control and mercury-treated embryos, which were subjected to mild hypotonic protein extraction, or immunostained to reveal nervous system morphology. Embryos left to develop into adults were examined for wing phenotypes. Relative to control metals, we found that mercury strongly inhibits in vitro γ-secretase processing of both amyloid-β precursor protein (APP) and Notch. Mercury inhibited APP and Notch cleavage in a dose-dependent manner, with IC(50) values of 50-125 nM, and is therefore comparable in potency to benchmark γ-secretase inhibitors. Immunoblot analysis of embryonic protein extracts showed that mercury inhibits Notch cleavage by γ-secretase in vivo. This is accompanied by severe neurodevelopmental abnormalities in embryos and adult wing-notching phenotypes. Our findings provide first evidence that mercury is a direct and potent γ-secretase inhibitor and suggest that inhibition of γ-secretase and disruption of the Notch developmental pathway potentially contribute to mercury-induced toxicity in the nervous system.
authors.affiliation: Brain Mind Institute, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Station 15, CH-1015 Lausanne, Switzerland.
authors.forename: Jean-René
authors.initials: JR
authors.lastname: Alattia
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kuraishi
authors.forename: Mitko
authors.initials: M
authors.lastname: Dimitrov
authors.forename: Isabelle
authors.initials: I
authors.lastname: Chang
authors.forename: Bruno
authors.initials: B
authors.lastname: Lemaitre
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Fraering
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D004151:Dipeptides / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000196:embryology / Q000254:growth & development; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D008628:Mercury / Q000633:toxicity*; D008767:Methylmercury Compounds / Q000633:toxicity; D009422:Nervous System Diseases / Q000139:chemically induced / Q000196:embryology / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D014921:Wings, Animal / Q000002:abnormalities / Q000187:drug effects / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D004151:Dipeptides; D029721:Drosophila Proteins; D008767:Methylmercury Compounds; C497759:N protein, Drosophila; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D008628:Mercury