Engrailed Homeoprotein Protects Mesencephalic Dopaminergic Neurons from Oxidative Stress

•Engrailed regulates DNA damage response and chromatin remodeling•Dopaminergic neurons are protected by Engrailed from oxidative stress•Engrailed acts both at genetic and epigenetic levels to confer neuroprotection•Engrailed homeoprotein transduction has therapeutic potential

SummaryEngrailed homeoproteins are expressed in adult dopaminergic neurons of the substantia nigra. In Engrailed1 heterozygous mice, these neurons start dying at 6 weeks, are more sensitive to oxidative stress, and progressively develop traits similar to those observed following an acute and strong oxidative stress inflected to wild-type neurons. These changes include DNA strand breaks and the modification (intensity and distribution) of several nuclear and nucleolar heterochromatin marks. Engrailed1 and Engrailed2 are biochemically equivalent transducing proteins previously used to antagonize dopaminergic neuron death in Engrailed1 heterozygous mice and in mouse models of Parkinson disease. Accordingly, we show that, following an acute oxidative stress, a single Engrailed2 injection restores all nuclear and nucleolar heterochromatin marks, decreases the number of DNA strand breaks, and protects dopaminergic neurons against apoptosis.

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