Age-dependent Motor Deficits and Dopaminergic Dysfunction in DJ-1 Null Mice

Abstract

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...

Oxidative Status of DJ-1-dependent Activation of Dopamine Synthesis through Interaction of Tyrosine Hydroxylase and 4-Dihydroxy-l-phenylalanine (l-DOPA) Decarboxylase with DJ-1

“…F and G, TH and DDC activities in cells were measured as described in the legends of DJ-1 knock-out mice, on the other hand, dopaminergic cell death did not occur, resulting in no reduction of dopamine content (29 -31). Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 knock-out mice have however been reported (31). We also confirmed no reduction of expression levels and activities of TH and DDC in DJ-1 knock-out mice (data not shown).…”

Stimulation of vesicular monoamine transporter 2 activity by DJ-1 in SH-SY5Y cells

“…Contrary to human cases of familial forms of Parkinson's disease caused by mutations of parkin, pink1 and DJ-1 genes, corresponding knockout mice, even triple knockout mice, do not show obvious phenotypes of Parkinson's disease [32]. There are no significant differences in TH, DDC and VMAT2 levels between wild-type and DJ-1-knockout mice [33]. Although the precise mechanisms underlying the absence of phenotypes in knockout mice are not clear, a compensation mechanism might be involved.…”

Transduced Tat-DJ-1 Protein Protects against Oxidative Stress-Induced SH-SY5Y Cell Death and Parkinson Disease in a Mouse Model

“…It is well known that DJ-1 has multiple functions including anti-oxidant and chaperone functions associated with PD pathogenesis (Menzies et al, 2005;Xu et al, 2005;Zhou et al, 2006). However, DJ-1 deficiency or loss-of-function leads to oxidative stressinduced cell death in vitro and in vivo (Chen et al, 2005;Goldberg et al, 2005;Kim et al, 2005). Although anti-oxidant enzymes have been considered as potential therapeutic agents against oxidative stress-mediated diseases, the enzymes inability to enter cells hinders this despite its apparent potential.…”