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Engrailed, an Anti-ageing Homeoprotein

出版	2015
URL	http://books.google.com.hk/books?id=PA4f0AEACAAJ&hl=&source=gbs_api

註釋Homeoproteins are morphogenetic transcription factors, which have cell and non-cell autonomous functions. For example, En1 and En2, collectively Engrailed (En), are important for midbrain dopaminergic (mDA) neuron development and crucial for their adult maintenance. En1+/- mice display a selective and progressive degeneration of the mDA neurons of the Substantia Nigra pars compacta (SNpc), reminiscent of Parkinson disease (PD). Furthermore, En infusion in the SNpc saves neurons in several models of the disease. In the case of MPTP, En-mediated neuroprotection partially necessitates its ability to upregulate the translation of Ndufs1, a subunit of the mitochondrial Complex I. The main aim of my thesis was to study additional neuroprotective pathways mediated by En. We first studied En1+/- mice and showed that neurodegeneration was accompanied by increased DNA damage and chromatin relaxation. In an acute oxidative stress model, similar but accelerated phenotypes were seen, which were antagonized by En injection. The En-mediated positive impact on these key hallmarks of ageing lends weight to the idea that En is a promising anti-ageing factor, possibly useful in the treatment of PD. Long interspersed nuclear elements (LINE-1) are a class of retrotransposons with the ability to multiply in the genome. Although considered silent, they are expressed in mouse mDA neurons and their expression is increased by an acute oxidative stress, leading to DNA damage and degeneration. Their direct repression by En allows us to propose that their transcriptional and/or epigenetic silencing explains part of En protective activity in mouse models of acute and progressive oxidative stress.