Engrailed protects mouse midbrain dopaminergic neurons against mitochondrial complex I insults

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Alvarez-Fischer, Daniel | Fuchs, Julia | Castagner, François | Stettler, Olivier | Massiani Beaudoin, Olivia | Moya, Kenneth L | Bouillot, Colette | Oertel, Wolfgang H | Lombès, Anne | Faigle, Wolfgang | Joshi, Rajiv L | Hartmann, Andreas | Prochiantz, Alain

Edité par CCSD ; Nature Publishing Group -

International audience. Mice heterozygous for homeobox gene Engrailed-1 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 PD in animals. Engrailed enhances the translation of nuclear-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 siRNA. 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 Engrailed-1 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.

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