Engrailed protects mouse midbrain dopaminergic neurons against mitochondrial complex I insults
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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 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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In dopaminergic neurons and retinal ganglion cell growth cones, translation of nuclear-encoded mitochondrial mRNAs commonly occurs after homeoprotein capture.
“Indeed, translation of nuclear-encoded mitochondrial mRNAs commonly follows homeoprotein capture by dopaminergic neurons or retinal ganglion cell growth cones (Alvarez-Fischer et al., 2011; Stettler et al., 2012; Yoon et al., 2012).”
From Choroid-Plexus-Derived Otx2 Homeoprotein Constrains Adult Cortical Plasticity (2013) · cites this paper as Alvarez-Fischer et al., 2011
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- Authors
- Alvarez-Fischer, D., Fuchs, J., Castagner, F., Stettler, O., Massiani-Beaudoin, O., Moya, K. L., Bouillot, C., Oertel, W. H., Lombès, A., Faigle, W., Joshi, R. L., Hartmann, A., & Prochiantz, A.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Philipps University of Marburg (DE)
- Inserm (FR)
- Institut Curie (FR)
- Corresponding author
- Joshi, Rajiv L
- Hartmann, Andreas
- Prochiantz, Alain
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2011-09-04
- Volume
- 14
- Issue
- 10
- Pages
- 1260-1266
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W2034104365
- Cited by
- 150
- References
- 51
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 9 · 2023: 9 · 2022: 9 · 2021: 7 · 2020: 10 · 2019: 13 · 2018: 9 · 2017: 10 · 2016: 7 · 2015: 15 · 2014: 13 · 2013: 13 · 2012: 11
- FWCI
- 7.91
- Type
- journal article
- Language
- en
- Open access
- green
- hal.science
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- HAL Portal Artxiker (Hindustan Aeronautics Limited (India)) (submittedVersion)
- Oskar-Bordeaux (Universite de Bordeaux) (submittedVersion)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Keywords
- EN1, Engrailed-2, homeodomain transcription factor, midbrain dopaminergic neurons, Parkinson's disease, MPTP-induced neurotoxicity, mitochondrial complex I, NDUFS1, NDUFS3, neuronal survival, substantia nigra pars compacta, 6-hydroxydopamine, striatal dopamine, neuroprotection
- MeSH terms
- Engrailed 2 Protein, Animals, Cell Count, Cells, Cultured, Chromatography, High Pressure Liquid, Dopamine, Embryo, Mammalian, Male, Mesencephalon, Mice, Inbred C57BL, Mice, Transgenic, NADH Dehydrogenase, Nerve Tissue Proteins, Neurons, Neurotoxins, Nitro Compounds, Propionates, Rotenone, Stereotyped Behavior, Tyrosine 3-Monooxygenase, Dizocilpine Maleate, Oxidopamine, Homeodomain Proteins, RNA, Small Interfering, Electron Transport Chain Complex Proteins, Dopamine Plasma Membrane Transport Proteins, Mice, alpha-Synuclein, In Vitro Techniques
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