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Engrailed homeoprotein blocks degeneration in adult dopaminergic neurons through LINE‐1 repression
Author(s) -
Blaudin de Thé FrançoisXavier,
Rekaik Hocine,
PezeHeidsieck Eugenie,
MassianiBeaudoin Olivia,
Joshi Rajiv L,
Fuchs Julia,
Prochiantz Alain
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201797374
Subject(s) - biology , engrailed , psychological repression , dopaminergic , degeneration (medical) , neuronal degeneration , neuroscience , line (geometry) , genetics , microbiology and biotechnology , gene , homeobox , transcription factor , dopamine , disease , medicine , gene expression , pathology , geometry , mathematics
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.