Long-lasting transcriptional refractoriness triggered by a single exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder whose etiology is thought to have environmental (toxin) and genetic contributions. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP) induces pathological features of PD including loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and striatal dopamine (DA) depletion. We previously described the striatal transcriptional response following acute MPTP administration in MPTP-sensitive C57BL/6J mice. We identified three distinct phases: early (5h), intermediate (24h) and late (72h) and reported that the intermediate and late responses were absent in MPTP-resistant Swiss-Webster (SWR) mice. Here we show that C57BL/6J mice pre-treated with a single 40mg/kg dose of MPTP and treated 9days later with 4×20mg/kg MPTP, display a striatal transcriptional response similar to that of MPTP-resistant SWR mice, i.e. a robust acute response but no intermediate or late response. Transcriptional refractoriness is dependent upon the dose of the priming challenge with as little as 10mg/kg MPTP being effective and can persist for more than 28days. Priming of SWR mice has no effect on their response to subsequent challenge with MPTP. We also report that paraquat, another free radical producer, also elicits striatal transcriptional alterations but these are largely distinct from those triggered by MPTP. Paraquat-induced changes are also refractory to priming with paraquat. However neither paraquat nor MPTP elicits cross-attenuation. Thus exposure to specific toxins triggers distinct transcriptional responses in striatum that are influenced by prior exposure to the same toxin. The prolonged refractory period described here for MPTP could explain at the molecular level the reported discrepancies between different MPTP administration regimens and may have implications for our understanding of the relationship between environmental toxin exposure and PD.