Engrailed homeoprotein blocks degeneration in adult dopaminergic neurons through LINE-1 repression

EMBO J. 2018 Aug 1;37(15):e97374. doi: 10.15252/embj.201797374. Epub 2018 Jun 25.


LINE-1 mobile genetic elements have shaped the mammalian genome during evolution. A minority of them have escaped fossilization which, when activated, can threaten genome integrity. We report that LINE-1 are expressed in substantia nigra ventral midbrain dopaminergic neurons, a class of neurons that degenerate in Parkinson's disease. In Engrailed-1 heterozygotes, these neurons show a progressive degeneration that starts at 6 weeks of age, coinciding with an increase in LINE-1 expression. Similarly, DNA damage and cell death, induced by an acute oxidative stress applied to embryonic midbrain neurons in culture or to adult midbrain dopaminergic neurons in vivo, are accompanied by enhanced LINE-1 expression. Reduction of LINE-1 activity through (i) direct transcriptional repression by Engrailed, (ii) a siRNA directed against LINE-1, (iii) the nucleoside analogue reverse transcriptase inhibitor stavudine, and (iv) viral Piwil1 expression, protects against oxidative stress in vitro and in vivo We thus propose that LINE-1 overexpression triggers oxidative stress-induced DNA strand breaks and that an Engrailed adult function is to protect mesencephalic dopaminergic neurons through the repression of LINE-1 expression.

Keywords: Engrailed adult functions; L1 retrotransposons; dopaminergic neurons; neurodegeneration; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Argonaute Proteins / genetics
  • Cell Line
  • DNA Breaks*
  • DNA Damage / genetics
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology*
  • HEK293 Cells
  • Homeodomain Proteins / genetics*
  • Humans
  • Long Interspersed Nucleotide Elements / genetics*
  • Mice
  • Mice, Transgenic
  • Oxidative Stress / genetics*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Regulatory Elements, Transcriptional / genetics
  • Substantia Nigra / metabolism


  • Argonaute Proteins
  • En1 protein, mouse
  • Homeodomain Proteins
  • Piwil1 protein, mouse
  • RNA, Small Interfering