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

被引:52
作者
de The, Francois-Xavier Blaudin [1 ]
Rekaik, Hocine [1 ]
Peze-Heidsieck, Eugenie [1 ]
Massiani-Beaudoin, Olivia [1 ]
Joshi, Rajiv L. [1 ]
Fuchs, Julia [1 ]
Prochiantz, Alain [1 ]
机构
[1] PSL Res Univ, Coll France, CIRB, INSERM,CNRS,UMR 7241,U1050, Paris 05, France
基金
欧洲研究理事会;
关键词
dopaminergic neurons; Engrailed adult functions; L1; retrotransposons; neurodegeneration; oxidative stress; L1; RETROTRANSPOSITION; TRANSPOSABLE ELEMENTS; OXIDATIVE STRESS; SMALL RNAS; PROTECTS; MOBILE; CELLS; HETEROCHROMATIN; TRANSLATION; INSTABILITY;
D O I
10.15252/embj.201797374
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 invivo, 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 invitro and invivo. 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.
引用
收藏
页数:19
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