Selective enrichment of DJ‐1 protein in primate striatal neuronal processes: Implications for Parkinson's disease

Abstract

Mutations in DJ-1 cause autosomal recessive, early-onset Parkinson's disease (PD). The precise function and distribution of DJ-1 in the central nervous system remain unclear. In this study, we performed a comprehensive analysis of DJ-1 expression in human, monkey, and rat brains using antibodies that recognize distinct, evolutionarily conserved epitopes of DJ-1. We found that DJ-1 displays region-specific neuronal and glial labeling in human and non-human primate brain, sharply contrasting the primarily neuronal expression pattern observed throughout rat brain. Further immunohistochemical analysis of DJ-1 expression in human and non-human primate brains showed that DJ-1 protein is expressed in neurons within the substantia nigra pars compacta and striatum, two regions critically involved in PD pathogenesis. Moreover, immunoelectron microscopic analysis revealed a selective enrichment of DJ-1 within primate striatal axons, presynaptic terminals, and dendritic spines with respect to the DJ-1 expression in prefrontal cortex. Together, these findings indicate neuronal and synaptic expression of DJ-1 in primate subcortical brain regions and suggest a physiological role for DJ-1 in the survival and/or function of nigral-striatal neurons. KeywordsPARK7; substantia nigra; striatum; electron microscopy; primate brain; distribution Parkinson's disease (PD) is a debilitating neurodegenerative movement disorder characterized by the relatively selective degeneration of nigral dopaminergic neurons (Lang and Lozano, 1998a;Lang and Lozano, 1998b). Recently, mutations in the gene encoding DJ-1 have been identified as the genetic defect responsible for the PARK7-associated autosomal recessive, early-onset form of familial PD (Abou-Sleiman et al., 2004;Bonifati et al., 2003). Accumulating evidence suggests that loss of DJ-1 function results in neurodegeneration, but the exact role of DJ-1 in the pathogenesis of PD is unknown (Cookson, 2005;Moore et al., 2005). Using X-ray crystallography, we and others have shown that DJ-1 is a 189 amino acid protein that adopts a helix-strand-helix dimeric structure with homology to the bacterial NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript protease PH1704 and Escherichia coli chaperone protein Hsp31 (Huai et al., 2003;Lee et al., 2003;Tao and Tong, 2003). Although the precise physiological function of DJ-1 remains unclear, DJ-1 has been implicated in several cellular processes including regulation of transcription, protein quality control, and oxidative stress response (Bonifati et al., 2004;Cookson, 2005;Moore et al., 2005). In addition, targeted disruption of DJ-1 gene expression in mice leads to altered dopamine D2 receptor signaling (Chen et al., 2005;Goldberg et al., 2005) and increased susceptibility to MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine)-induced neurodegeneration (Kim et al., 2005).The distribution of DJ-1 protein is controversial and remains poorly characterized. We previously showed that DJ-1 is mainly neuronal in cortical and subcor...

DJ-1 Decreases Bax Expression through Repressing p53 Transcriptional Activity

“…Increased levels of p53 and phosphorylated p53 were found in the substantia nigra and striatum of the postmortem PD brains (34,35); DJ-1 is also selectively expressed within these two regions critically involved in PD pathogenesis (36,37). Interestingly, our study demonstrates that the protective effects of DJ-1 are not caused by the change of p53 levels but by inhibiting p53 transcriptional activities.…”

Mechanisms of DJ‐1 neuroprotection in a cellular model of Parkinson’s disease

“…Alternatively, different subsets of DJ-1-interacting proteins may be available in cells subjected to different insults, resulting in the formation of protein complexes with different functional outputs. Another unresolved question is whether the protective mechanisms of DJ-1 in our mixed cultures and in human brain are activated preferentially in neurons or glia, given that the protein is abundant in both cell types (Bandopadhyay et al 2004;Olzmann et al 2007). In this study, we showed via immunocytochemical staining that DJ-1-mediated upregulation of iHsp70 in MG132-treated cultures occurs in dopaminergic and non-dopaminergic neurons and in glia.…”

The role of α-synuclein in neurodegeneration — An update

“…DJ-1 downregulation enhances cell death by OS, ER stress, and proteasome inhibition [234], while the localization of DJ-1 to mitochondria is associated with protective actions against some mitochondrial poisons [235]. Exogenously applied DJ-1 was shown to localize to mitochondria, the cytosol, nucleus, and microsomes [227,231,232], while endogenous DJ-1, locating to presynaptic terminals of striatal axons and dendrites [236], revealed interaction with membranes of cultured cells [237]. Furthermore, DJ-1 partly colocalizes with the synaptic marker Rab3A at synaptic terminals, which suggests interaction with membrane trafficking [238].…”