Journal
NATURE NEUROSCIENCE
Volume 14, Issue 10, Pages 1260-U182Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.2916
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Funding
- Agence Nationale pour la Recherche [ANR-06-013-01]
- Michael. J. Fox Foundation (MJFF)
- Fondation de France
- European Community [222999]
- University Medical Center Giessen and Marburg (UKGM)
- German Academic Exchange Service (DAAD)
- German Research Foundation (DFG)
- FRM
- NERF (Neuropole de Recherche Francilien)
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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 alpha-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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