Strain-dependent susceptibility to MPTP and MPP(+)-induced parkinsonism is determined by glia.
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.
Smeyne
M
M
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38015, USA.
Goloubeva
O
O
Smeyne
R J
RJ
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004298:Dopamine / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D006540:Herbicides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013045:Species Specificity; D013378:Substantia Nigra / Q000166:cytology
D015259:Dopamine Agents; D006540:Herbicides; D017382:Reactive Oxygen Species; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine