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

Abstract 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 Parkinson9s 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.