The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson's disease

Abstract

Two mutations in the DJ-1 gene on chromosome1p36 have been identified recently to cause early-onset, autosomal recessive Parkinson's disease. As no information is available regarding the distribution of DJ-1 protein in the human brain, in this study we used a monoclonal antibody for DJ-1 to map its distribution in frontal cortex and substantia nigra, regions invariably involved in Parkinson's disease. Western blotting of human frontal cortex showed DJ-1 to be an abundant protein in control, idiopathic Parkinson's disease, cases with clinical and pathological phenotypes of Parkinson's disease with R98Q polymorphism for DJ-1, and in progressive supranuclear palsy (PSP) brains. We also showed that DJ-1 immunoreactivity (IR) was particularly prominent in astrocytes and astrocytic processes in both control and Parkinson's disease frontal cortex, whereas neurons showed light or no DJ-1 IR. Only occasional Lewy bodies (LBs), the pathological hallmarks of Parkinson's disease, showed faint DJ-1 IR, localized to the outer halo. In preclinical studies we showed that DJ-1 is expressed in primary hippocampal and astrocyte cultures of mouse brain. By 2D gel analysis we also showed multiple pI isoforms for DJ-1 ranging between 5.5-6.6 in both control and Parkinson's disease brains, whilst exposure of M17 cells to the oxidizing agent paraquat was manifested as a shift in pI of endogenous DJ-1 towards more acidic isoforms. We conclude that DJ-1 is not an essential component of LBs and Lewy neurites, is expressed mainly by astrocytes in human brain tissue and is sensitive to oxidative stress conditions. These results are consistent with the hypothesis that neuronal-glial interactions are important in the pathophysiology of Parkinson's disease.

Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging

“…6). The profiles of DJ-1 protein in control vs. late-onset Parkinson's patients support this idea, where increased levels of modified DJ-1 are seen (42,43). Increased modification of C104 (C106 in hDJ-1) may functionally impair DJ-1 activity, leading to decreased protein function.…”

“…Recent findings of increased acidic isoforms of DJ-1 in the brains of Parkinson's patients support a role for DJ-1 modification in sporadic disease (42,43). Therefore, we addressed DJ-1 modification and potential effects on function in vivo using Drosophila.…”

DJ-1 binds to mitochondrial complex I and maintains its activity

“…DJ-1 has three cysteines at amino acid numbers 46, 53 and 106 (C46, C53 and C106, respectively). Although oxidation of C106 is necessary for DJ-1 to exert its activity [11][12][13], further oxidation of C106 is thought to render DJ-1 inactive [14], and such oxidized DJ-1 has been observed in patients with the sporadic form of PD and Alzheimer disease [15,16].…”

The caspase 6 derived N-terminal fragment of DJ-1 promotes apoptosis via increased ROS production

“…8 The level of expression of DJ-1 controls the cell death and survival balance in neurodegenerative diseases or cell survival in cancer and rare deletion or loss of function mutations in DJ-1 gene have been linked to autosomal recessive EOPD. 9,10 Point mutations or deletion of DJ-1 gene yield proteins with decreased stability and thereby, abolish their protective and survival-associated functions. In addition, in several models of cancer cells, DJ-1 expression is increased and positively associated with the severity of the disease.…”