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Nat Neurosci. 2011 Sep 4;14(10):1260-6. doi: 10.1038/nn.2916.

Engrailed protects mouse midbrain dopaminergic neurons against mitochondrial complex I insults.

Author information

1
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.

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.

PMID:
21892157
DOI:
10.1038/nn.2916
[Indexed for MEDLINE]

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