Engrailed protects mouse midbrain dopaminergic neurons against mitochondrial complex I insults

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Count / methods
  • Cells, Cultured
  • Chromatography, High Pressure Liquid / methods
  • Dizocilpine Maleate / pharmacology
  • Dopamine / metabolism*
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Electron Transport Chain Complex Proteins / metabolism
  • Embryo, Mammalian
  • Homeodomain Proteins / metabolism*
  • Homeodomain Proteins / pharmacology
  • In Vitro Techniques
  • Male
  • Mesencephalon / cytology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NADH Dehydrogenase / pharmacology
  • Nerve Tissue Proteins / metabolism*
  • Nerve Tissue Proteins / pharmacology
  • Neurons / drug effects
  • Neurons / physiology*
  • Neurotoxins / toxicity*
  • Nitro Compounds / toxicity
  • Oxidopamine / toxicity
  • Propionates / toxicity
  • RNA, Small Interfering / pharmacology
  • Rotenone / toxicity
  • Stereotyped Behavior / drug effects
  • Tyrosine 3-Monooxygenase / metabolism
  • alpha-Synuclein / metabolism

Substances

  • Dopamine Plasma Membrane Transport Proteins
  • Electron Transport Chain Complex Proteins
  • En1 protein, mouse
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • Neurotoxins
  • Nitro Compounds
  • Propionates
  • RNA, Small Interfering
  • alpha-Synuclein
  • engrailed 2 protein
  • Rotenone
  • Dizocilpine Maleate
  • Oxidopamine
  • Tyrosine 3-Monooxygenase
  • NADH Dehydrogenase
  • 3-nitropropionic acid
  • Dopamine