Mutations in parkin are currently recognized as the most common cause of familial Parkinsonism. Emerging evidence also suggests that parkin expression variability may confer a risk for the development of the more common, sporadic form of Parkinson's disease (PD). Supporting this, we have recently demonstrated that parkin solubility in the human brain becomes altered with age. As parkin apparently functions as a broad-spectrum neuroprotectant, the resulting decrease in the availability of soluble parkin with age may underlie the progressive susceptibility of the brain to stress. Interestingly, we also observed that many familial-PD mutations of parkin alter its solubility in a manner that is highly reminiscent of our observations with the aged brain. The converging effects on parkin brought about by aging and PD-causing mutations are probably not trivial and suggest that environmental modulators affecting parkin solubility would increase an individual's risk of developing PD. Using both cell culture and in vivo models, we demonstrate here that several PD-linked stressors, including neurotoxins (MPP+, rotenone, 6-hydroxydopamine), paraquat, NO, dopamine and iron, induce alterations in parkin solubility and result in its intracellular aggregation. Furthermore, the depletion of soluble, functional forms of parkin is associated with reduced proteasomal activities and increased cell death. Our results suggest that exogenously introduced stress as well as endogenous dopamine could affect the native structure of parkin, promote its misfolding, and concomitantly compromise its protective functions. Mechanistically, our results provide a link between the influence of environmental and intrinsic factors and genetic susceptibilities in PD pathogenesis.

BackgroundIt has long been postulated that the relative abundance of specific nutrients can affect cognitive processes and emotions. Newly described influences of dietary factors on neuronal function and synaptic plasticity have revealed some of the vital mechanisms that could be responsible for the action of diet on brain health and cognitive function. Here, through a double-blind, randomized, placebo-controlled trial, we asked if the newly discovered chicken meat ingredient-168 (CMI-168) could be beneficial to the cognitive function in healthy adults.MethodsNormal, healthy subjects were supplemented with either placebo or CMI-168 for 6 weeks. The subjects were given a series of cognitive tests to examine their levels of cognitive functioning at the beginning and end of supplementation, as well as two weeks after termination of supplementation. The combination of these tests, namely Digit Span Backwards, Letter-Number Sequencing, and the Rey Auditory Verbal Learning Test (RAVLT), was used to assess the subjects’ attention and working memory. For all comparisons, the probability level of p < 0.05 was taken as statistically significant using repeated measure 2-way ANOVA followed by Bonferroni post-hoc test.ResultsOverall, subjects supplemented with CMI-168 showed significantly (p < 0.01) better performance in all cognitive tests after 6 weeks’ supplementation compared to control and such superior performance was maintained even 2 weeks after termination of supplementation.ConclusionsThe present study reveals the cognition-enhancing properties of a recently developed chicken meat ingredient, likely arising from the promotion of attention and prefrontal cortex functions.

Parkinson disease (PD), a prevalent neurodegenerative motor disorder, is characterized by the rather selective loss of dopaminergic neurons and the presence of ␣-synuclein-enriched Lewy body inclusions in the substantia nigra of the midbrain. Although the etiology of PD remains incompletely understood, emerging evidence suggests that dysregulated iron homeostasis may be involved. Notably, nigral dopaminergic neurons are enriched in iron, the uptake of which is facilitated by the divalent metal ion transporter DMT1. To clarify the role of iron in PD, we generated SH-SY5Y cells stably expressing DMT1 either singly or in combination with wild type or mutant ␣-synuclein. We found that DMT1 overexpression dramatically enhances Fe 2؉ uptake, which concomitantly promotes cell death. This Fe 2؉ -mediated toxicity is aggravated by the presence of mutant ␣-synuclein expression, resulting in increased oxidative stress and DNA damage. Curiously, Fe 2؉ -mediated cell death does not appear to involve apoptosis. Instead, the phenomenon seems to occur as a result of excessive autophagic activity. Accordingly, pharmacological inhibition of autophagy reverses cell death mediated by Fe 2؉ overloading. Taken together, our results suggest a role for iron in PD pathogenesis and provide a mechanism underlying Fe 2؉ -mediated cell death.Parkinson disease (PD) 3 is the most common motor neurodegenerative disorder, affecting 1-2% of the population over the age of 65. Pathologically, it is characterized by selective dopaminergic neuron loss and the presence of Lewy bodies immunoreactive for ␣-synuclein in the substantia nigra pars compacta. To date, the leading causes for the sporadic form of the disease remain unclear, although there is accumulating evidence implicating oxidative stress (1), including the finding that PD brains have increased levels of oxidative damage to DNA, proteins, and lipids (2-4). One potential player contributing to increased oxidative stress is iron, which can convert hydrogen peroxide to highly reactive hydroxyl radicals via the Fenton reaction. Indeed, increased deposition of iron was found in microglia, astrocytes, oligodendrocytes, and dopaminergic neurons of the substantia nigra pars compacta of post-mortem PD brains (5, 6). The total iron content was found to be significantly higher in the substantia nigra pars compacta of PD patients together with a corresponding increase in divalent metal transporter-1 (DMT1) transcripts in the same region (7). This suggests a close association among DMT1 expression, iron overload, and PD.Mutations in a number of genes have also been implicated in the pathogenesis of PD (8) of which the first to be discovered was ␣-synuclein. Besides the A53T, A30P, and E46K missense mutations (9 -11), duplication (12, 13) and triplication (14) of the ␣-synuclein gene have also been linked to familial forms of PD. It has been suggested that the tendency of ␣-synuclein to undergo misfolding and aggregation may underlie its involvement in Lewy body formation and hence PD (15). Given that i...

Exposure to divalent metals such as iron and manganese is thought to increase the risk for Parkinson’s disease (PD). Under normal circumstances, cellular iron and manganese uptake is regulated by the divalent metal transporter 1 (DMT1). Accordingly, alterations in DMT1 levels may underlie the abnormal accumulation of metal ions and thereby disease pathogenesis. Here, we have generated transgenic mice overexpressing DMT1 under the direction of a mouse prion promoter and demonstrated its robust expression in several regions of the brain. When fed with iron-supplemented diet, DMT1-expressing mice exhibit rather selective accumulation of iron in the substantia nigra, which is the principal region affected in human PD cases, but otherwise appear normal. Alongside this, the expression of Parkin is also enhanced, likely as a neuroprotective response, which may explain the lack of phenotype in these mice. When DMT1 is overexpressed against a Parkin null background, the double-mutant mice similarly resisted a disease phenotype even when fed with iron- or manganese-supplemented diet. However, these mice exhibit greater vulnerability toward 6-hydroxydopamine-induced neurotoxicity. Taken together, our results suggest that iron accumulation alone is not sufficient to cause neurodegeneration and that multiple hits are required to promote PD.Electronic supplementary materialThe online version of this article (doi:10.1007/s12017-017-8451-0) contains supplementary material, which is available to authorized users.

Activation of nontransmembrane protein tyrosine kinases (PTKs), phosphatidylinositol 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) has been shown to be responsible for high-affinity Fc receptor (Fcepsilon RI)-mediated mast cell degranulation. Effects of inhibitors of the PTK signaling cascade on ovalbumin (OA)-induced anaphylactic contraction of isolated guinea-pig bronchi and release of histamine and peptidoleukotrienes from chopped lung preparations were studied. Genistein (30 microM) and tyrphostin 47 (50 microM), two PTK inhibitors, as well as LY294002 (10 microM), a selective PI3K inhibitor, significantly reduced (p < 0.05) peak anaphylactic bronchial contraction and facilitated relaxation of the contracted bronchi. PD 098059 (30 microM), a selective MAPK kinase inhibitor, failed to suppress OA-induced peak bronchial contraction, but facilitated the relaxation of the contracted bronchi (p < 0.05). At the same concentrations, none of these inhibitors showed any inhibitory effects on histamine-, leukotriene D(4) (LTD(4))- or KCl-induced bronchial contraction. On the other hand, these inhibitors significantly prevented (p < 0.05) OA-induced release of both histamine and peptidoleukotrienes from chopped lung preparations. In addition, combined PD 098059 and LY294002 treatment markedly (p < 0.05) suppressed the peak anaphylactic bronchial contraction and facilitated relaxation of the contracted bronchi. The combination of these two inhibitors further inhibited the release of peptidoleukotrienes from chopped lung preparations. Taken together, our data show that inhibition of tyrosine kinase signaling cascade can markedly attenuate anaphylactic contraction of airways, probably via inhibition of mast cell degranulation, and that inhibitors of this signaling cascade may have therapeutic potential for the treatment of asthma.