NRF2-dependent antioxidants and DJ-1 expression was negatively associated with severity of COPD. Therapy directed toward enhancing NRF2-regulated antioxidants may be a novel strategy for attenuating the effects of oxidative stress in the pathogenesis of COPD.

Mutations in

Mutations in the DJ-1 gene were recently identified in an autosomal recessive form of early-onset familial Parkinson disease. Structural biology, biochemistry, and cell biology studies have suggested potential functions of DJ-1 in oxidative stress, protein folding, and degradation pathways. However, animal models are needed to determine whether and how loss of DJ-1 function leads to Parkinson disease. We have generated DJ-1 null mice with a mutation that resembles the large deletion mutation reported in patients. Our behavioral analyses indicated that DJ-1 deficiency led to age-dependent and taskdependent motoric behavioral deficits that are detectable by 5 months of age. Unbiased stereological studies did not find obvious dopamine neuron loss in 6-month-and 11-month-old mice. Neurochemical examination revealed significant changes in striatal dopaminergic function consisting of increased dopamine reuptake rates and elevated tissue dopamine content. These data represent the in vivo evidence that loss of DJ-1 function alters nigrostriatal dopaminergic function and produces motor deficits.Mutations in DJ-1 were recently identified in an autosomal recessive form of early-onset familial Parkinson disease (PD) 1 (1). The first reported mutation involves one large deletion of the first 5 exons and part of the promoter and another mutation was a missense mutation (L166P) that might cause instability of the DJ-1 protein by preventing it from folding properly and forming homodimers (2-5). Since this first report, a number of other mutations of DJ-1 including deletion mutations, point mutations, and a frameshift mutation have been found to cause PD (6 -10). These studies suggest that the loss of the normal function of DJ-1 leads to PD.However, the nature of the normal function of DJ-1 and the mechanism by which DJ-1 deficiency leads to PD are not well established. Studies prior to the report of its association with PD suggested that DJ-1 might play a role in oncogenesis (11), male fertility (12, 13), control of protein-RNA interaction (14), and in modulating androgen receptor transcription activity (15,16). In addition, the DJ-1 protein was shown to be responsive to oxidation (17, 18), suggesting a potential role in oxidative stress, a process often implicated in PD. Studies on PD-linked DJ-1 mutations indicate that wild-type, but not mutant, DJ-1 protects cells from oxidative stress (19 -21). Canet-Aviles et al. (22) reported that oxidation of the Cys 106 residue in DJ-1 could lead to its relocalization in mitochondria and protect cells from mitochondrial damage. Structurally, DJ-1 closely resembles the members of the ThiJ/PfpI family that have protease and chaperone activities (23-27). Recent biochemical studies suggested that DJ-1 might have protease (5) and redox-dependent chaperone activities (28). Therefore, putative functions of DJ-1 seem to converge on the common pathogenesis of PD implicated in other genetic and sporadic forms of PD.Despite those new insights into the biochemical and cellular functions of DJ-1, th...

Mitochondrial dysfunction has been reported in both familial and sporadic Parkinson’s disease (PD). However, effective therapy targeting this pathway is currently inadequate. Recent studies suggest that manipulating the processes of mitochondrial fission and fusion has considerable potential for treating human diseases. To determine the therapeutic impact of targeting these pathways on PD, we used two complementary mouse models of mitochondrial impairments as seen in PD. We show here that blocking mitochondrial fission is neuroprotective in the PTEN-induced putative kinase-1 deletion (PINK1−/−) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models. Specifically, we show that inhibition of the mitochondrial fission GTPase dynamin-related protein-1 (Drp1) using gene-based and small molecule approaches attenuates neurotoxicity and restores pre-existing striatal dopamine release deficits in these animal models. These results suggest Drp1 inhibition as a potential treatment for PD.

The role of dopamine as a vulnerability factor and a toxic agent in Parkinson's disease (PD) is still controversial, yet the presumed dopamine toxicity is partly responsible for the "DOPA-sparing" clinical practice that avoids using L-3,4-dihydroxyphenylalanine (L-DOPA), a dopamine precursor, in early PD. There is a lack of studies on animal models that directly isolate dopamine as one determining factor in causing neurodegeneration. To address this, we have generated a novel transgenic mouse model in which striatal neurons are engineered to take up extracellular dopamine without acquiring regulatory mechanisms found in dopamine neurons. These mice developed motor dysfunctions and progressive neurodegeneration in the striatum within weeks. The neurodegeneration was accompanied by oxidative stress, evidenced by substantial oxidative protein modifications and decrease in glutathione. Ultrastructural morphologies of degenerative cells suggest necrotic neurodegeneration. Moreover, L-DOPA accelerated neurodegeneration and worsened motor dysfunction. In contrast, reducing dopamine input to striatum by lesioning the medial forebrain bundle attenuated motor dysfunction. These data suggest that pathology in genetically modified striatal neurons depends on their dopamine supply. These neurons were also supersensitive to neurotoxin. A very low dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (5 mg/kg) caused profound neurodegeneration of striatal neurons, but not midbrain dopamine neurons. Our results provide the first in vivo evidence that chronic exposure to unregulated cytosolic dopamine alone is sufficient to cause neurodegeneration. The present study has significant clinical implications, because dopamine replacement therapy is the mainstay of PD treatment. In addition, our model provides an efficient in vivo approach to test therapeutic agents for PD.