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Manganese (Mn) is an environmental risk factor for Parkinson's disease (PD). Recessive inheritance of PARK2 mutations is strongly associated with early onset PD (EOPD). It is widely assumed that the influence of PD environmental risk factors may be enhanced by the presence of PD genetic risk factors in the genetic background of individuals. However, such interactions may be difficult to predict owing to the complexities of genetic and environmental interactions. Here we examine the potential of human induced pluripotent stem (iPS) cell-derived early neural progenitor cells (NPCs) to model differences in Mn neurotoxicity between a control subject (CA) with no known PD genetic risk factors and a subject (SM) with biallelic loss-of-function mutations in PARK2 and family history of PD but no evidence of PD by neurological exam. Human iPS cells were generated from primary dermal fibroblasts of both subjects. We assessed several outcome measures associated with Mn toxicity and PD. No difference in sensitivity to Mn cytotoxicity or mitochondrial fragmentation was observed between SM and CA NPCs. However, we found that Mn exposure was associated with significantly higher reactive oxygen species (ROS) generation in SM compared to CA NPCs despite significantly less intracellular Mn accumulation. Thus, this report offers the first example of human subject-specific differences in PD-relevant environmental health related phenotypes that are consistent with pathogenic interactions between known genetic and environmental risk factors for PD.
Copyright © 2012 Elsevier Inc. All rights reserved.
Ceruloplasmin is a protective ferroxidase. Although some studies suggest that plasma ceruloplasmin levels are raised by exercise, the impact of exercise on brain ceruloplasmin is unknown. We have examined whether striatal ceruloplasmin is raised with treadmill exercise and/or is correlated with spontaneous physical activity in rhesus monkeys. Parkinson's disease is characterized by a loss in ceruloplasmin and, similarly, Parkinson's models lead to a loss in antioxidant defenses. Exercise might protect against Parkinson's disease and is known to prevent antioxidant loss in experimental models. We have therefore examined whether treadmill exercise prevents ceruloplasmin loss in monkeys treated unilaterally with the dopaminergic neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). We found that exercise raised ceruloplasmin expression in the caudate and accumbens but not the putamen of intact monkeys. However, putamen ceruloplasmin was correlated with spontaneous activity in a home pen. MPTP alone did not cause unilateral loss of ceruloplasmin but blocked the impact of exercise on ceruloplasmin. Similarly, the correlation between putamen ceruloplasmin and activity was also lost with MPTP. MPTP elicited loss of tyrosine hydroxylase in the treated hemisphere; the remaining tyrosine hydroxylase was correlated with overall daily activity (spontaneous activity plus that induced by the treadmill). Thus, treadmill activity can raise ceruloplasmin but this impact and the link with spontaneous activity are both diminished in Parkinsonian primates. Furthermore, low overall physical activity predicts greater loss of dopaminergic phenotype in MPTP-treated primates. These data have implications for the maintenance of active lifestyles in both healthy and neurodegenerative conditions.
We are testing the hypothesis that exercise is neuroprotective in animal models of the dopamine (DA) deficiency in Parkinson's disease. Our studies include mice or rats provided access to a running wheel and subsequently treated with MPTP (mice) or 6-hydroxydopamine (rats) and monkeys provided access to a treadmill and subsequently treated with MPTP. Typically, the exercise occurs for 3 months prior to the toxin treatment and often for 1-2 months thereafter. Our findings indicate that exercise reduces the behavioral impairments elicited by the dopaminergic neurotoxins as well as the loss of DA neurons as assessed by PET imaging and biochemical or histochemical assessment of tissue samples. Our studies are focused on one of several possible explanations for the beneficial effects of exercise: an exercise-induced increase in the expression of neurotrophic factors, particularly GDNF. Our observations indicate that GDNF can reduce the vulnerability of DA neurons, in part due to the activation of key intracellular cascades. We also find that mild cellular stress itself can provide protection against more intensive stress, a form of preconditioning. We conclude that dopamine neurons have the capacity to respond to intracellular and extracellular signals by triggering endogenous neuroprotective mechanisms. This raises the possibility that some individuals with Parkinson's disease suffer from a reduction of these neuroprotective mechanisms, and that treatments that boost these mechanisms - including exercise - may provide therapeutic benefit.
Exposure to pesticides has been suggested to increase the risk of Parkinson's disease (PD), but the mechanisms responsible for this association are not clear. Here, we report that perinatal exposure of mice during gestation and lactation to low levels of dieldrin (0.3, 1, or 3 mg/kg every 3 days) alters dopaminergic neurochemistry in their offspring and exacerbates MPTP toxicity. At 12 wk of age, protein and mRNA levels of the dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) were increased by perinatal dieldrin exposure in a dose-related manner. We then administered MPTP (2 x 10 mg/kg s.c) at 12 wk of age and observed a greater reduction of striatal dopamine in dieldrin-exposed offspring, which was associated with a greater DAT:VMAT2 ratio. Additionally, dieldrin exposure during development potentiated the increase in GFAP and alpha-synuclein levels induced by MPTP, indicating increased neurotoxicity. In all cases there were greater effects observed in the male offspring than the female, similar to that observed in human cases of PD. These data suggest that developmental exposure to dieldrin leads to persistent alterations of the developing dopaminergic system and that these alterations induce a "silent" state of dopamine dysfunction, thereby rendering dopamine neurons more vulnerable later in life.
The cAMP response element-binding protein (CREB) is believed to play a pivotal role in dopamine (DA) receptor-mediated nuclear signaling and neuroplasticity. Here we demonstrate that the significance of CREB for gene expression depends on the experimental paradigm. We compared the role of CREB in two different but related models: l-DOPA administration to unilaterally 6-hydroxydopamine lesioned rats, and cocaine administration to neurologically intact animals. Antisense technology was used to produce a local knockdown of CREB in the lateral caudate-putamen, a region that mediates the dyskinetic or stereotypic manifestations associated with l-DOPA or cocaine treatment, respectively. In intact rats, CREB antisense reduced both basal and cocaine-induced expression of c-Fos, FosB/DeltaFosB, and prodynorphin mRNA. In the DA-denervated striatum, CREB was not required for l-DOPA to induce these gene products, nor did CREB contribute considerably to DNA binding activity at cAMP responsive elements (CREs) and CRE-like enhancers. DeltaFosB-related proteins and JunD were the main contributors to both CRE and AP-1 DNA-protein complexes in l-DOPA-treated animals. In behavioral studies, intrastriatal CREB knockdown caused enhanced activity scores in intact control animals and exacerbated the dyskinetic effects of acute l-DOPA treatment in 6-OHDA-lesioned animals. These data demonstrate that CREB is not required for the development of l-DOPA-induced dyskinesia in hemiparkinsonian rats. Moreover, our results reveal an unexpected alteration of nuclear signaling mechanisms in the parkinsonian striatum treated with l-DOPA, where AP-1 transcription factors appear to supersede CREB in the activation of CRE-containing genes.
Functional MRI (fMRI) was used to study striatal sensitivity to levodopa in hemiparkinsonian rhesus monkeys. Responses consistent with increased neuronal activity were seen in areas whose normal dopaminergic input from the substantia nigra pars compacta had been ablated by MPTP. Sites of increased activity following levodopa included the lateral putamen, the ventral region of the caudate head, septal areas, and midlateral amygdala in the MPTP-lesioned hemisphere. Increased activity was also observed in the same areas in the nonlesioned hemisphere, but was less pronounced in spatial extent and magnitude, suggesting either subclinical contralateral damage and/or functional adaptations in the contralateral dopamine systems. The increases in neuronal activity following levodopa treatment were temporally correlated with increases in striatal dopamine levels. Chronic levodopa treatment reduced behavioral responsiveness to levodopa and abolished the fMRI response. These results suggest that fMRI can detect changes in dopamine receptor-mediated neuronal sensitivity to dopaminergic agents.
Principal component analysis (PCA) is one of several structure-seeking multivariate statistical techniques, exploratory as well as inferential, that have been proposed recently for the characterization and detection of activation in both PET and fMRI time series data. In particular, PCA is data driven and does not assume that the neural or hemodynamic response reaches some steady state, nor does it involve correlation with any pre-defined or exogenous experimental design template. In this paper, we present a generalized linear systems framework for PCA based on the singular value decomposition (SVD) model for representation of spatio-temporal fMRI data sets. Statistical inference procedures for PCA, including point and interval estimation will be introduced without the constraint of explicit hypotheses about specific task-dependent effects. The principal eigenvectors capture both the spatial and temporal aspects of fMRI data in a progressive fashion; they are inherently matched to unique and uncorrelated features and are ranked in order of the amount of variance explained. PCA also acts as a variation reduction technique, relegating most of the random noise to the trailing components while collecting systematic structure into the leading ones. Features summarizing variability may not directly be those that are the most useful. Further analysis is facilitated through linear subspace methods involving PC rotation and strategies of projection pursuit utilizing a reduced, lower-dimensional natural basis representation that retains most of the information. These properties will be illustrated in the setting of dynamic time-series response data from fMRI experiments involving pharmacological stimulation of the dopaminergic nigro-striatal system in primates.
A multiple Gradient Recalled Echo MRI sequence was used to map spatial and temporal changes in the rate of MR signal decay (R2*) in response to L-3,4-dihydroxyphenylalanine (levodopa) in the striatal dopaminergic system of a rhesus monkey unilaterally lesioned with 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP). R2* decreased significantly in the right (dopamine depleted) putamen and caudate following levodopa. More focal areas of smaller R2* decline were also observed in these structures in the left hemisphere. The observed spatial and temporal patterns of R2* change support the view that the method is monitoring changes in neural activity.
Fetal substantia nigra cells of two different gestational ages were successfully transplanted into the brains of three methylphenyltetrahydropyridine-treated monkeys with severe parkinsonian motor and behavioural deficits. Functional improvement continued for 10 weeks after cell grafts into the striata of two monkeys with substantial numbers of tyrosine-hydroxylase-positive fetal neurons at necropsy. Behavioural improvement was correlated with increases in cerebrospinal fluid (CSF) homovanillic acid (HVA) concentrations after the transplants. A control monkey with inappropriately placed transplanted cells of an earlier gestational age remained severely parkinsonian and died during a similar period. CSF HVA fell slightly in this monkey from the low level seen before the transplants. Fetal dopamine neurons of two different gestational ages appear to survive transplantation in primates and have biochemical and functional effects.