Prefrontal cortical functioning depends on D1 family receptors and their complex signal transduction cascade, including protein phosphatase-1 (PP1). Three PP1 isoforms are prominent in the brain: PP1alpha, PP1beta and PP1gamma1. PP1 localization by a variety of scaffolding proteins is critical for dopamine-mediated modulation of glutamatergic neurotransmission. We have quantified the subcellular distribution of each isoform in primate prefrontal cortex using immunoelectron microscopy. All three are found in spines, dendrites, axon terminals, axons and glia. However, PP1alpha and PP1gamma1 labeling is enriched in spines, whereas PP1beta label is enriched in dendrites. Using post-embedding immunogold labeling, we further examined the distribution of PP1alpha and PP1gamma1 within spines. PP1gamma1 is highly and specifically concentrated in the postsynaptic density (PSD) of these spines, while PP1alpha is enriched in the PSD but also found subjacent to the PSD in moderate amounts. Thus, PP1 isoforms are heterogeneously distributed in the cortical neuropil and within spines. These results suggest that each PP1 isoform has access to a different set of substrates and, furthermore, they demonstrate that the composition of signal transduction proteins varies in different parts of the neuron and even in different regions of a dendritic spine in the primate PFC.

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...