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Strain-dependent susceptibility to MPTP and MPP(+)-induced parkinsonism is determined by glia
M Smeyne1, O Goloubeva, R J Smeyne
1Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38015, USA.
Abstract:
Parkinson's disease (PD) is a debilitating neurological disorder that strikes approximately 2% of people over age 50. Current hypotheses propose that the cause of PD is multifactorial, involving environmental agents and genetic predisposition. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces parkinsonism in many species, including humans and shows strain specificity in mice. The mechanism of strain specificity, however, remains unknown. Using novel chimeric murine substantia nigra cultures, we demonstrate that sensitivity to MPTP is conferred by glia and that it does not involve the MAO-B conversion of MPTP to MPP(+). C57Bl/6J dopaminergic neurons exposed to MPP(+) demonstrated a 39% loss when cultured on C57Bl/6J glia compared with 17% neuron loss when cultured on resistant SWR/J glia. Similarly, SWR/J neurons exposed to MPP(+) demonstrated a 4% loss when cultured on SWR/J glia, but a 14% loss when cultured on sensitive C57Bl/6J glia. The identification of glia as the critical cell type in the genesis of experimental Parkinsonism provides a target for the development of new anti-parkinsonian therapies.
Insights
Glial cells, not neurons, determine sensitivity to MPTP, a toxin causing Parkinsonism. This finding reveals glia as a key target for developing new Parkinson's disease therapies.
Area of Science:
- Neuroscience
- Toxicology
- Genetics
Background:
- Parkinson's disease (PD) affects 2% of individuals over 50.
- PD is thought to result from genetic and environmental factors.
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces parkinsonism, but its strain-specific mechanism in mice is unclear.
Purpose of the Study:
- To investigate the mechanism of MPTP strain specificity in experimental parkinsonism.
- To identify the critical cell type responsible for MPTP sensitivity.
Main Methods:
- Utilized novel chimeric murine substantia nigra cultures.
- Co-cultured dopaminergic neurons and glia from MPTP-sensitive (C57Bl/6J) and resistant (SWR/J) mouse strains.
- Assessed neuronal loss after exposure to MPP+, the toxic metabolite of MPTP.
Main Results:
- MPTP sensitivity is conferred by glial cells, not dopaminergic neurons.
- C57Bl/6J neurons showed significantly higher MPP+-induced loss when cultured on C57Bl/6J glia compared to SWR/J glia.
- SWR/J neurons showed minimal loss on SWR/J glia but increased loss on C57Bl/6J glia.
- The MAO-B conversion of MPTP to MPP+ was not involved in the observed strain specificity.
Conclusions:
- Glial cells are the critical determinants of susceptibility to MPTP-induced neurotoxicity.
- This discovery identifies glia as a potential therapeutic target for Parkinson's disease.
- Understanding glial roles may lead to novel anti-parkinsonian treatments.