Interactions Between Environmental and Genetic Factors in the Pathophysiology of Parkinson's Disease

Tsang, Fai; Soong, Tuck Wah

doi:10.1080/1521654031000153058

Cited by 16 publications

(7 citation statements)

References 31 publications

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“…Further research is needed to address these questions. Overall, the data presented here parallel physiological events that lead to more severe stages of neurodegeneration in diseases like Alzheimer and Parkinson (Aksenov et al, 2001;Tsang and Soong, 2003). Thus, our findings indicate that the bee may emerge as a valuable model in neurogerontological research.…”

Section: Discussionsupporting

confidence: 71%

Cellular senescence in honey bee brain is largely independent of chronological age

Seehuus

Krekling

Amdam

2006

Experimental Gerontology

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Accumulation of oxidative stress-induced damage in brain tissue plays an important role in the pathogenesis of normal aging and neurodegenerative diseases. Neuronal oxidative damage typically increases with age in humans, and also in the invertebrate and vertebrate model species most commonly used in aging research. By use of quantitative immunohistochemistry and Western blot, we show that this aspect of brain senescence is largely decoupled from chronological age in the honey bee (Apis mellifera). The bee is a eusocial insect characterized by the presence of a reproductive queen caste and a caste of functionally sterile female workers that performs various alloparental tasks such as nursing and foraging. We studied patterns of oxidative nitration and carbonylation damage in the brain of worker bees that performed nurse tasks as 8-and 200-day-olds and foraging tasks as 20-and 200-day-olds. In addition, we examined 180-day-old diutinus bees, a stress-resistant temporal worker form that survives unfavorable periods. Our results indicate that nitration damage occurs only at low levels in vivo, but that a 60-kDa protein from honey bee brain is selectively nitrated by peroxynitrite in vitro. Oxidative carbonylation is present at varying levels in the visual and chemosensory neuropiles of worker bees, and this inter-individual variation is better explained by social role than by chronological age.

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Section: Discussionsupporting

confidence: 71%

Cellular senescence in honey bee brain is largely independent of chronological age

Seehuus

Krekling

Amdam

2006

Experimental Gerontology

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“…The etiology of PD is thought to involve interplay between environmental agents and genetic risk factors (Poirier et al, 1991,Tsang and Soong, 2003,Allam et al, 2005. A number of inbred strains of mice with differential sensitivity to MPTP have been identified and can be used to identify genetic factors (Hamre et al, 1999,Schwarting et al, 1999,Smeyne et al, 2001,Cook et al, 2003,Liu et al, 2003a,McLaughlin et al, 2006.…”

Section: Discussionmentioning

confidence: 99%

Temporal mRNA profiles of inflammatory mediators in the murine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine model of Parkinson’s disease

2007

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). With the exception of a few rare familial forms of the disease, the precise molecular mechanisms underlying PD are unknown. Inflammation is a common finding in the PD brain, but due to the limitation of postmortem analysis its relationship to disease progression cannot be established. However, studies using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD have also identified inflammatory responses in the nigrostriatal pathway that precede neuronal degeneration in the SNpc. To assess the pathological relevance of these inflammatory responses and to identify candidate genes that might contribute to neuronal vulnerability, we used quantitative reverse-transcription polymerase chain reaction (qRT-PCR) to measure mRNA levels of 11 cytokine and chemokine encoding genes in the striatum of MPTP-sensitive (C57BL/6J) and MPTP-insensitive (Swiss Webster, SWR) mice following administration of MPTP. The mRNA levels of all 11 genes changed following MPTP treatment, indicating the presence of inflammatory responses in both strains. Furthermore, of the 11 genes examined only 3, interleukin 6 (Il-6), macrophage inflammatory protein 1 alpha/CC chemokine ligand 3 (Mip-1alpha/Ccl3) and macrophage inflammatory protein 1 beta/CC chemokine ligand 4 (Mip-1beta/Ccl4), were differentially regulated between C57BL/6J and SWR mice. In both mouse strains, the level of monocyte chemoattractant protein 1/CC chemokine ligand 2 (Mcp-1/Ccl2) mRNA was the first to increase following MPTP administration, and might represent a key initiating component of the inflammatory response. Using Mcp-1/Ccl2 knockout mice backcrossed onto a C57BL/6J background we found that MPTP-stimulated Mip-1alpha/Ccl3 and Mip-1beta/Ccl4 mRNA expression was significantly lower in the knockout mice; suggesting that Mcp-1/Ccl2 contributes to MPTP-enhanced expression of Mip-1alpha/Ccl3 and Mip-1beta/Ccl4. However, stereological analysis of SNpc neuronal loss in Mcp-1/Ccl2 knockout and wild-type mice showed no differences. These findings suggest that it is the ability of dopaminergic SNpc neurons to survive an inflammatory insult, rather than genetically determined differences in the inflammatory response itself, that underlie the molecular basis of MPTP resistance.

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“…Given that iron increases the propensity of ␣-synuclein to aggregate (16,17), it is tempting to speculate on a synergistic effect between the two. In line with this, there is a growing consensus that the combinatorial effects of environmental and genetic factors may underlie neuronal vulnerability in PD (18).…”

mentioning

confidence: 96%

Enhanced Autophagy from Chronic Toxicity of Iron and Mutant A53T α-Synuclein

Chew

Ang

Tai

et al. 2011

Journal of Biological Chemistry

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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...

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Interactions Between Environmental and Genetic Factors in the Pathophysiology of Parkinson's Disease

Cited by 16 publications

References 31 publications

Cellular senescence in honey bee brain is largely independent of chronological age

Cellular senescence in honey bee brain is largely independent of chronological age

Temporal mRNA profiles of inflammatory mediators in the murine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine model of Parkinson’s disease

Enhanced Autophagy from Chronic Toxicity of Iron and Mutant A53T α-Synuclein

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