In response to oxidative stress, the nuclear factor E2-related factor 2 (Nrf2) transcription factor translocates from the cytoplasm into the nucleus and transactivates expression of genes with antioxidant activity. Despite this cellular mechanism, oxidative damage is abundant in Alzheimer and Parkinson disease (AD and PD). To investigate mechanisms by which Nrf2 activity may be aberrant or insufficient in neurodegenerative conditions, we assessed Nrf2 localization in affected brain regions of AD, Lewy body variant of AD (LBVAD), and PD. By immunohistochemistry, Nrf2 is expressed in both the nucleus and the cytoplasm of neurons in normal hippocampi with predominant expression in the nucleus. In AD and LBVAD, Nrf2 was predominantly cytoplasmic in hippocampal neurons and was not a major component of beta amyloid plaques or neurofibrillary tangles. By immunoblotting, we observed a significant decrease in nuclear Nrf2 levels in AD cases. In contrast, Nrf2 was strongly nuclear in PD nigral neurons but cytoplasmic in substantia nigra of normal, AD, and LBVAD cases. These findings suggest that Nrf2-mediated transcription is not induced in neurons in AD despite the presence of oxidative stress. In PD, nuclear localization of Nrf2 is strongly induced, but this response may be insufficient to protect neurons from degeneration.

A variety of mutations in the gene encoding DJ-1 protein are causal of autosomal recessive early-onset parkinsonism. Recently, a novel pathogenic homozygous DJ-1 missense mutation resulting in the L10P amino acid substitution was reported. In a separate study, a novel homozygous mutation resulting in the deletion of DJ-1 residue P158 was also reported to be causative of disease. The specific effects of the novel L10P and P158DEL mutations on protein function have not been studied. Herein, L10P and P158DEL DJ-1 proteins were assessed for protein stability, dimerization, solubility, subcellular localization, and protective function in comparison to WT and the L166P DJ-1 pathogenic variant. It was discovered that in comparison to WT protein, L10P, L166P, and P158DEL DJ-1 variants exhibited dramatically reduced protein stabilities. Degradation of each of the respective pathogenic mutants appeared to be mediated in-part by the proteasome. Interestingly, unlike L166P DJ-1, the L10P and P158DEL DJ-1 variants retained the ability to dimerize with WT DJ-1 protein; however, neither of these mutants was able to form homodimers. Additionally, the L10P, L166P, and P158DEL DJ-1 variants exhibited altered profiles on size-exclusion chromatography and demonstrated reduced solubilities in comparison to WT protein, and the latter aberration could be exacerbated in the presence of MG-132. Further, cells stably expressing L10P DJ-1 were more vulnerable to treatments with proteasome inhibitors, suggesting that L10P DJ-1 may be toxic to cells under conditions of proteasome stress. Taken together, these findings suggest that diverse aberrant mechanisms, including alterations in protein stability and protein folding, are associated with the pathogenicity of the L10P and P158DEL DJ-1 variants.

Parkinson’s disease (PD) is a neurodegenerative movement disorder that results from the progressive loss of dopaminergic neurons in the midbrain substantia nigra pars compacta (SNpc). The specific molecular events that cause PD are currently not known; however, progress to better understand PD pathogenesis has been made using various animal models of the disease. In this review, we have highlighted reports from 2012 in which neurochemical/neurotoxins have been used in rodents to specifically address the role of neuroinflammation in the development and/or progression of PD-like pathology and in particular nigral degeneration. A number of studies have been summarized in which plausible pro-inflammatory, anti-inflammatory, or therapeutic agents targeting inflammatory pathways were introduced and/or investigated by various groups for neuroprotective effects. From these studies, it is clear that neuroinflammation acts to exacerbate the toxic outcomes that are set in motion within neurons following exposure to neurotoxins. Additionally, it is noted that future work is still needed to better understand the underlying mechanisms mediating the neuroinflammatory and neurotoxic phenotypes reported in rodent models of PD-like pathology to maximize the translation potential of these interventions to the clinic to prevent and/or delay PD onset and/or progression in humans.

Recent discoveries of genetic mutations linked to familial forms of Parkinson's disease (PD), including mutations in DJ-1, have provided insights into the pathogenesis of sporadic PD. Recently, a novel homozygous missense mutation in the gene encoding human DJ-1 protein resulting in the E163K amino acid substitution has been reported. This mutation is associated with early-onset and clinical presentations that include parkinsonism, cognitive decline, and amyotrophic lateral sclerosis. The specific effect of this mutation on the function of DJ-1 protein as it relates to disease pathogenesis is currently unknown. Herein we show that the E163K pathogenic mutant retains similar properties to wild-type DJ-1 protein as it relates to protein stability, solubility, and dimerization. However, we show that the E163K mutant loses the ability to protect against oxidative stress while demonstrating a reduced redistribution towards mitochondria, but retains the ability to mitigate toxicity due to mitochondrial stress and proteasomal impairment. These findings suggest that DJ-1 influences several neuroprotective pathways and that the E163K mutation impairs the mechanism that is more specific to oxidative stress.