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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Hauser, David N; Mamais, Adamantios; Conti, Melissa M et al. (2017) Hexokinases link DJ-1 to the PINK1/parkin pathway. Mol Neurodegener 12:70
Hauser, David N; Primiani, Christopher T; Cookson, Mark R (2017) The Effects of Variants in the Parkin, PINK1, and DJ-1 Genes along with Evidence for their Pathogenicity. Curr Protein Pept Sci 18:702-714
Cookson, Mark R (2017) RNA-binding proteins implicated in neurodegenerative diseases. Wiley Interdiscip Rev RNA 8:
Hauser, David N; Dillman, Allissa A; Ding, Jinhui et al. (2014) Post-translational decrease in respiratory chain proteins in the Polg mutator mouse brain. PLoS One 9:e94646
Prahlad, Janani; Hauser, David N; Milkovic, Nicole M et al. (2014) Use of cysteine-reactive cross-linkers to probe conformational flexibility of human DJ-1 demonstrates that Glu18 mutations are dimers. J Neurochem 130:839-53
Cookson, Mark R (2012) Parkinsonism due to mutations in PINK1, parkin, and DJ-1 and oxidative stress and mitochondrial pathways. Cold Spring Harb Perspect Med 2:a009415
McCoy, Melissa K; Cookson, Mark R (2011) DJ-1 regulation of mitochondrial function and autophagy through oxidative stress. Autophagy 7:531-2
Hauser, David N; Cookson, Mark R (2011) Astrocytes in Parkinson's disease and DJ-1. J Neurochem 117:357-8
Thomas, Kelly Jean; McCoy, Melissa K; Blackinton, Jeff et al. (2011) DJ-1 acts in parallel to the PINK1/parkin pathway to control mitochondrial function and autophagy. Hum Mol Genet 20:40-50
Cookson, Mark R (2010) Unravelling the role of defective genes. Prog Brain Res 183:43-57

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