Kumaran, R. (2009) Characterisation of DJ1 (PARK7) in human brain: possible involvement in idiopathic Parkinson's disease and other neurodegenerative disorders. Doctoral thesis, UCL (University College London).
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Mutations in the DJ‐1 gene can induce the development of early‐onset Parkinson's disease (PD) through a loss of protein function. Currently any possible role for DJ‐1 in sporadic PD remains undetermined. To address this, we have studied the characteristics and activities of DJ‐1 in post‐mortem human brain tissue in order to gain insights into its contribution to the development of PD and other neurodegenerative disorders. Western blotting revealed DJ‐1 protein expression to be reduced in several brain regions associated with PD pathology including nigra, striatum and frontal cortex. Similarly levels of DJ‐1 mRNA were also shown to also be lower in PD striatum and frontal cortex suggesting a transcriptional regulation of protein expression in human brain. Further analysis of DJ‐1 gene expression showed PD related changes to be variable throughout the brain, with regions like the amygdala and entorhinal cortex displaying an up‐regulation. DJ‐1 protein was also shown to undergo increased oxidation in PD cases, highlighting the elevated oxidative stress conditions in PD. By using immunoprecipitation to investigate a possible role for DJ‐1 as an in vivo regulator of translation, we found DJ‐1 protein associates with RNA transcripts for selenoproteins, PTEN/Akt pathway components and mitochondrial subunits of complex 1. Protein levels for a number of these transcripts were altered in PD tissue without any parallel change in mRNA levels. DJ‐1 is reportedly involved in a diverse range of cellular activities and its proclivity to associate with multiple RNA species provides a simple biochemical mechanism for this. Moreover it demonstrates that under conditions of elevated oxidative stress, DJ‐1 can instigate a rapid and compartmentalised up‐regulation of pro‐survival proteins in a transcriptionally independent manner. Analysis of DJ‐1 in tauopathies showed co‐localisation with 3R and 4R tau, implicating a possible chaperone function for DJ‐1. Unlike in PD, no altered expression of DJ‐1 mRNA and protein was observed.
|Title:||Characterisation of DJ1 (PARK7) in human brain: possible involvement in idiopathic Parkinson's disease and other neurodegenerative disorders|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > Molecular Neuroscience|
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