DJ-1 and hexokinases

多年来，我们一直对氧化应激与DJ-1（隐性帕金森病的罕见病因）之间的关系感兴趣，并重点关注氧化应激与线粒体定位之间的关系。我们发现，在大鼠和小鼠的大脑中，DJ-1敲除导致细胞质中己糖激酶1的年龄依赖性积累，远离其在线粒体的通常位置，随后激活体内葡萄糖代谢的多元醇途径。在大脑和培养细胞中，DJ-1缺乏与磷酸酶PTEN的积累有关，PTEN可拮抗AKT激酶。在细胞中，添加AKT抑制剂（MK2206）或添加肽来解离线粒体中己糖激酶的关联，都抑制了维持线粒体完整性的PINK1/parkin通路。

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.