Synergistic effects of environmental risk factors and gene mutations in Parkinson’s disease accelerate age‐related neurodegeneration

Abstract

As Parkinson’s disease appears to be a multifactoral disorder, the use of animal models to investigate combined effects of genetic and environmental risk factors are of great importance especially in the context of aging which is the single major risk factor for the disorder. Here, we assessed the combined effects of neonatal iron feeding and environmental paraquat exposure on age-related nigrostriatal degeneration in transgenic mice expressing the A53T familial mutant form of human α-synuclein within these neurons. We report here that A53T α-synuclein mice exhibit greater susceptibility to paraquat. Increased oral intake of iron in the neonatal period leads to a progressive age-related enhancement of dopaminergic neurodegeneration associated with paraquat neurotoxicity. Furthermore, neurodegeneration associated with these combined genetic and environmental risk factors could be attenuated by systemic treatment with the bioavailable antioxidant compound EUK-189. These data suggest that environmental factors previously identified as contributors to neurodegeneration associated with sporadic Parkinson’s disease may also be candidates for observed variations in symptoms and disease progression in monogenic forms and that this may mechanistically involve increased levels of oxidatively-induced post-translational nitration of α-synuclein.

Parkinson’s Disease

“…Brooks et al 1999; Manning-Bog et al 2001, 2002; Norris et al 2007)). While paraquat exposure has not been shown to foster Lewy body formation, it does accelerate α-synuclein misfolding (Uversky et al 2001), enhances membrane conductance disruption with dopamine (Feng and Maguire-Zeiss 2011) or proteasome disruption (Yang and Tiffany-Castiglioni 2007) in α-synuclein overexpressing cell lines and accelerates protein aggregation, inclusion formation and neuronal degeneration in transgenic mice that over-express α-synuclein (Manning-Bog et al 2002; Fernagut et al 2007; Peng et al 2010). Rotenone similarly enhances α-synuclein fibril formation in in vitro systems, while it increases α-synuclein modification, misfolding and toxicity in cultured cells (Orth et al 2003; Mirzaei et al 2006; Borland et al 2008; Lu et al 2010; Ma et al 2011).…”

High-performance metabolic profiling with dual chromatography-Fourier-transform mass spectrometry (DC-FTMS) for study of the exposome

“…Unfortunately, a large extent of the metabolome is still unidentified, especially many of the chemicals in the diet, as well as persistent organic pollutants and chemicals derived from commercial products, household products and health behaviors. Links between such exposures and human diseases have already been identified (Howell and Mangum 2010; Peng et al 2010; Lewis et al 2007; Ziech et al 2010; Gilmour et al 2006), and systematic collection of information on these exposures by improved metabolic profiling could be instrumental to characterization of the summation of these exposures, termed the “exposome” (Wild 2005) and use in personalized medicine and predictive health (Loscalzo et al 2007; Brigham 2010; Voit 2009). Therefore, the aim of this study was to increase overall metabolic detection in order to capture a larger extent of the exposome.…”

PARK2 patient neuroprogenitors show increased mitochondrial sensitivity to copper

“…decreased Cu chaperone capacity leading to increases in free Cu levels). Further study will be needed to investigate whether this gene by toxicant interaction is specific to Cu or if it occurs for a broad range of oxidative stressors, such as iron or mitochondrial inhibitors, which are also implicated as environmental modifiers or risk factors for parkinsonism (Peng et al, 2010; Saini et al, 2010; Ved et al, 2005). …”