LINE-1 repression attenuates degeneration in adult dopaminergic neurons

Long Interspersed Nuclear Elements (LINEs) retrotransposons are emerging as possible players in development and disease. We report here that the three main active LINE-1 families are expressed in post-mitotic dopaminergic neurons of the substantia nigra pars compacta, a class of ventral midbrain neurons that degenerate in Parkinson disease. The progressive degeneration of dopaminergic neurons in mice heterozygote for Engrailed-1 that starts at 6 weeks of age is paralleled by an increase in LINE-1 expression. Similarly, DNA damage and cell death induced by an acute oxidative stress specifically applied to these neurons is accompanied by enhanced LINE-1 expression. Following these observations, we demonstrate that LINE-1 overexpression is key to oxidative stress-induced neuronal death. Reduction of LINE-1 activity through direct transcriptional repression by Engrailed, a siRNA directed against LINE-1, the nucleoside-analogue reverse transcriptase inhibitor stavudine or viral Piwil1 expression, protects dopaminergic neurons against degeneration.