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

François-Xavier Blaudin de Thé, Hocine Rekaik, Eugenie Peze-Heidsieck, Olivia Massiani-Beaudoin, Rajiv L. Joshi, Julia Fuchs, Alain Prochiantz
doi: https://doi.org/10.1101/164608
François-Xavier Blaudin de Thé
1Centre for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS UMR 7241/INSERM U1050, PSL Research University, 11 place Marcelin Berthelot, 75231 Paris Cedex 05, France
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Hocine Rekaik
1Centre for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS UMR 7241/INSERM U1050, PSL Research University, 11 place Marcelin Berthelot, 75231 Paris Cedex 05, France
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Eugenie Peze-Heidsieck
1Centre for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS UMR 7241/INSERM U1050, PSL Research University, 11 place Marcelin Berthelot, 75231 Paris Cedex 05, France
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Olivia Massiani-Beaudoin
1Centre for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS UMR 7241/INSERM U1050, PSL Research University, 11 place Marcelin Berthelot, 75231 Paris Cedex 05, France
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Rajiv L. Joshi
1Centre for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS UMR 7241/INSERM U1050, PSL Research University, 11 place Marcelin Berthelot, 75231 Paris Cedex 05, France
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Julia Fuchs
1Centre for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS UMR 7241/INSERM U1050, PSL Research University, 11 place Marcelin Berthelot, 75231 Paris Cedex 05, France
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  • For correspondence: Julia.fuchs@college-de-france.fr
Alain Prochiantz
1Centre for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS UMR 7241/INSERM U1050, PSL Research University, 11 place Marcelin Berthelot, 75231 Paris Cedex 05, France
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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 Parkinson 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.

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Posted May 05, 2018.
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Engrailed homeoprotein blocks degeneration in adult dopaminergic neurons through LINE-1 repression
François-Xavier Blaudin de Thé, Hocine Rekaik, Eugenie Peze-Heidsieck, Olivia Massiani-Beaudoin, Rajiv L. Joshi, Julia Fuchs, Alain Prochiantz
bioRxiv 164608; doi: https://doi.org/10.1101/164608
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Engrailed homeoprotein blocks degeneration in adult dopaminergic neurons through LINE-1 repression
François-Xavier Blaudin de Thé, Hocine Rekaik, Eugenie Peze-Heidsieck, Olivia Massiani-Beaudoin, Rajiv L. Joshi, Julia Fuchs, Alain Prochiantz
bioRxiv 164608; doi: https://doi.org/10.1101/164608

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