title: Engrailed protects mouse midbrain dopaminergic neurons against mitochondrial complex I insults.
abstract: Mice heterozygous for the homeobox gene Engrailed-1 (En1) display progressive loss of mesencephalic dopaminergic (mDA) neurons. We report that exogenous Engrailed-1 and Engrailed-2 (collectively Engrailed) protect mDA neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a mitochondrial complex I toxin used to model Parkinson's disease in animals. Engrailed enhances the translation of nuclearly encoded mRNAs for two key complex I subunits, Ndufs1 and Ndufs3, and increases complex I activity. Accordingly, in vivo protection against MPTP by Engrailed is antagonized by Ndufs1 small interfering RNA. An association between Engrailed and complex I is further confirmed by the reduced expression of Ndufs1 and Ndufs3 in the substantia nigra pars compacta of En1 heterozygous mice. Engrailed also confers in vivo protection against 6-hydroxydopamine and α-synuclein-A30P. Finally, the unilateral infusion of Engrailed into the midbrain increases striatal dopamine content, resulting in contralateral amphetamine-induced turning. Therefore, Engrailed is both a survival factor for adult mDA neurons and a regulator of their physiological activity.
authors: Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière University Pierre and Marie Curie/Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S 975, Paris, France.
authors: Daniel
authors: D
authors: Alvarez-Fischer
authors: Julia
authors: J
authors: Fuchs
authors: François
authors: F
authors: Castagner
authors: Olivier
authors: O
authors: Stettler
authors: Olivia
authors: O
authors: Massiani-Beaudoin
authors: Kenneth L
authors: KL
authors: Moya
authors: Colette
authors: C
authors: Bouillot
authors: Wolfgang H
authors: WH
authors: Oertel
authors: Anne
authors: A
authors: Lombès
authors: Wolfgang
authors: W
authors: Faigle
authors: Rajiv L
authors: RL
authors: Joshi
authors: Andreas
authors: A
authors: Hartmann
authors: Alain
authors: A
authors: Prochiantz
mesh_terms: D000818:Animals; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004622:Embryo, Mammalian; D018398:Homeodomain Proteins / Q000378:metabolism* / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008636:Mesencephalon / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009245:NADH Dehydrogenase / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000633:toxicity*; D009574:Nitro Compounds / Q000633:toxicity; D016627:Oxidopamine / Q000633:toxicity; D011422:Propionates / Q000633:toxicity; D034741:RNA, Small Interfering / Q000494:pharmacology; D012402:Rotenone / Q000633:toxicity; D013239:Stereotyped Behavior / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism; D000099266:Engrailed 2 Protein
chemical_list: D016291:Dizocilpine Maleate; D004298:Dopamine; D050483:Dopamine Plasma Membrane Transport Proteins; D045222:Electron Transport Chain Complex Proteins; D018398:Homeodomain Proteins; D009245:NADH Dehydrogenase; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D009574:Nitro Compounds; D016627:Oxidopamine; D011422:Propionates; D034741:RNA, Small Interfering; D012402:Rotenone; D014446:Tyrosine 3-Monooxygenase; D051844:alpha-Synuclein; D000099266:Engrailed 2 Protein; C080330:En1 protein, mouse; C015392:3-nitropropionic acid