DJ-1 and hexokinases

多年来，我们一直对氧化应激与DJ-1（一种罕见的隐性帕金森病病因）之间的关系感兴趣，并专注于氧化应激与线粒体定位之间的关系。我们已经发现，在大鼠和小鼠的大脑中，DJ-1敲除导致己糖激酶1在细胞质中的年龄依赖性积累，远离其通常在线粒体的位置，随后激活体内葡萄糖代谢的多元醇途径。在脑和培养的细胞中，DJ-1缺乏与磷酸酶PTEN的积累有关，该磷酸酶PTEN拮抗激酶AKT。在细胞中，添加AKT抑制剂（MK 2206）或添加肽以使己糖激酶与线粒体的结合解离都抑制PINK 1/parkin途径，其用于维持线粒体完整性。 基因敲除动物中这些代谢变化的一个后果可能是晚期糖基化终产物在DNA、RNA和蛋白质上的积累。DJ-1最近被认为是这些物种的deglycase，因此我们在去年花了一些时间评估这一假设。我们确实看到了癌细胞中糖基化产物的改变，但目前正在评估我们是否也在体内模型中看到了相同的变化。

We have been interested in the relationship between oxidative stress and DJ-1, a rare cause of recessive Parkinson's disease, for several years and have focussed the relationship between oxidative stress and mitochondrial localization. We have found that in both rat and mouse brains, DJ-1 knockout results in an age-dependent accumulation of hexokinase 1 in the cytosol, away from its usual location at the mitochondria, with subsequent activation of the polyol pathway of glucose metabolism in vivo. Both in the brain and in cultured cells, DJ-1 deficiency is associated with accumulation of the phosphatase PTEN that antagonizes the kinase AKT. In cells, addition of an inhibitor of AKT (MK2206) or addition of a peptide to dissociate association of hexokinases from mitochondria both inhibit the PINK1/parkin pathway, which works to maintain mitochondrial integrity. One consequence of these metabolic changes in knockout animals is likely to be accumulation of advanced glycation endproducts on DNA, RNA and protein. DJ-1 has recently been suggested to be a deglycase for such species and so we have spent some time in the last year evaluating this hypothesis. We do see alterations in glycation products in cancer cells, but are currently evaluating whether we also see the same changes in in vivo models.