Long-lasting transcriptional refractoriness triggered by a single exposure to
R Pattarini1, Y Rong, K R Shepherd
1Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
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 40 mg/kg dose of MPTP and treated 9 days later with 4×20 mg/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 28 days. 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.
Insights
Prior exposure to MPTP toxin can cause temporary resistance to its effects on the brain, influencing Parkinson's disease research. This phenomenon, known as transcriptional refractoriness, affects how the striatum responds to subsequent toxin challenges.
Area of Science:
- Neuroscience
- Toxicology
- Genetics
Background:
- Parkinson's disease (PD) involves genetic and environmental factors, including neurotoxins like MPTP.
- MPTP induces PD-like pathology, including dopaminergic neuron loss.
- Previous studies identified distinct striatal transcriptional phases after MPTP exposure in mice.
Purpose of the Study:
- Investigate the effect of prior MPTP exposure on subsequent transcriptional responses.
- Determine the duration and dose-dependency of MPTP-induced refractoriness.
- Compare MPTP's transcriptional effects with paraquat and assess cross-attenuation.
Main Methods:
- Administered MPTP to C57BL/6J mice, followed by a second challenge after a delay.
- Analyzed striatal transcriptional responses at different time points.
- Primed MPTP-resistant Swiss-Webster (SWR) mice and assessed paraquat responses.
Main Results:
- MPTP pre-treatment induced a refractory period in C57BL/6J mice, eliminating intermediate and late transcriptional responses.
- This refractoriness was dose-dependent and persisted for over 28 days.
- Paraquat induced distinct transcriptional changes, also refractory to priming, with no cross-attenuation with MPTP.
Conclusions:
- Prior exposure to MPTP creates a prolonged refractory state in the striatum, impacting transcriptional responses.
- This refractoriness may explain variability in PD research using different MPTP administration protocols.
- Distinct toxins induce unique transcriptional signatures, and responses are modulated by prior exposure to the same toxin.
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