Abstract
The etiology of the vast majority of Parkinson's disease (PD) cases is unknown. It is generally accepted that there is an interaction between exposures to environmental agents with underlying genetic sensitivity. Recent epidemiological studies have shown that people living in agricultural communities have an increased risk of PD. Within these communities, paraquat (PQ) is one of the most utilized herbicides. PQ acts as a direct redox cycling agent to induce formation of free radicals and when administered to mice induces the cardinal symptoms of parkinsonism, including loss of TH+-positive dopaminergic (DA) neurons in the ventral midbrain's substantia nigra pars compacta (SNpc). Here we show that PQ-induced SNpc neuron loss is highly dependent on genetic background: C57BL/6J mice rapidly lose ∼50% of their SNpc DA neurons, whereas inbred Swiss-Webster (SWR/J) mice do not show any significant loss. We intercrossed these two strains to map quantitative trait loci (QTLs) that underlie PQ-induced SNpc neuron loss. Using genome-wide linkage analysis we detected two significant QTLs. The first is located on chromosome 5 (Chr 5) centered near D5Mit338, whereas the second is on Chr 14 centered near D14Mit206. These two QTLs map to different loci than a previously identified QTL (Mptp1) that controls a significant portion of strain sensitivity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), suggesting that the mechanism of action of these two parkinsonian neurotoxins are different.
Highlights
Parkinson’s disease (PD) is the third most common neurodegenerative disorder, affecting approximately two percent of the adult population older than 55 years
We have previously shown that these strains were respectively susceptible and resistant to MPTP-induced substantia nigra pars compacta (SNpc) dopamine neuron loss [19]
Genotypes were entered for each marker and correlated to two phenotypes: (1) the overall phenotypic severity treated as a Mendelian score, and (2) the number of SNpc DA neurons [15]
Summary
Parkinson’s disease (PD) is the third most common neurodegenerative disorder, affecting approximately two percent of the adult population older than 55 years. One mechanism related to environmental exposure that has been proposed in PD’s etiology is the abnormal handling of free radical species; whether by excessive generation of these species or inability to handle their detoxification [5,6]. Several animal models of PD that utilize xenobiotics have been developed; each mimicking aspects of parkinsonism. These include administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone or 1,19 di methyl-4,49-bipyridium dichloride (paraquat, PQ). Each of these toxins generates free radicals, the mechanism(s) by which this occurs is different. Paraquat generates free radicals, but through direct redox cycling [8,9]
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