Engrailed protects mouse midbrain dopaminergic neurons against mitochondrial complex I insults

Daniel Alvarez-Fischer (1) , Julia Fuchs (1) , François Castagner (1) , Olivier Stettler (1) , Olivia Massiani Beaudoin (1) , Kenneth L Moya (1) , Colette Bouillot (1) , Wolfgang H Oertel (1) , Anne Lombès (1) , Wolfgang Faigle (1) , Rajiv L Joshi (1) , Andreas Hartmann (1) , Alain Prochiantz (2)

1 CIRB - Centre interdisciplinaire de recherche en biologie
2 Collège de France - Chaire Processus morphogénétiques

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.

Mots clés: Signal Transduction; Neurological Disorders; Development; Neurodegeneration

Domaines: Neurosciences [q-bio.NC]

Daniel Alvarez-Fischer, Julia Fuchs, François Castagner, Olivier Stettler, Olivia Massiani Beaudoin, et al.. Engrailed protects mouse midbrain dopaminergic neurons against mitochondrial complex I insults. Nature Neuroscience, 2011, ⟨10.1038/nn.2916⟩. ⟨hal-00676206⟩