Genetic correlational analysis reveals no association between MPP+ and the severity of striatal dopaminergic damage following MPTP treatment in BXD mouse strains

Abstract

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a pro-neurotoxicant that must be metabolized to 1-methyl-4-phenylpyridinium (MPP(+)) and taken up into striatal dopaminergic neurons to produce neurodegeneration. Recently, we showed wide genetic variability in MPTP-associated neuronal damage in a panel of recombinant inbred mouse strains. Here we examined the amount of MPP(+) produced in the striatum in the same strains of inbred BXD mice. This allowed us to determine if the differences in the dopaminergic neurotoxicity and associated astrogliosis among the BXD mouse strains were due to differential metabolism of MPTP to MPP(+). Using the same BXD mouse strains examined previously (Jones et al., 2013) we found that the extent of the striatal damage produced following MPTP treatment is not correlated quantitatively with the production of MPP(+) in the striatum. Our findings also extend those of others regarding strain differences in MPTP-induced dopaminergic neurotoxicity. Importantly, our finding suggests that additional factors influence the neurodegenerative response other than the presence and amount of the toxicant at the target site.

MPTP neurotoxicity is highly concordant between the sexes among BXD recombinant inbred mouse strains

“…By using systems genetics, we showed that the extent of MPP+ production was quantitatively unrelated to the extent of DA loss in the striatum and showing once again that MPTP neurotoxicity is highly complex and determined by multiple factors (Jones et al, 2014). There is evidence showing the possible involvement of other enzymes such as mitochondrial cytochrome P450 2D6 (CYP2D6) in addition to monoamine oxidase B (MAOB) in the metabolism of MPTP to MPP+ (Bajpai et al, 2012).…”

Toxicogenetics: in search of host susceptibility to environmental toxicants

“…Knowing that the production of MPP+ is crucial to neurological destruction, we asked the question as to whether the extent of DA loss in the striatum is directly related to the amount of MPP+ produced. Comparing the mean loss of DA with the mean production of MPP+ the correlation was -0.15 and not significant at 7 degrees of freedom ( Jones et al, 2014b ). This illustrates one of the advantages of forward genetic analysis using a systems perspective.…”