Differential strain susceptibility following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration acts in an autosomal dominant fashion: quantitative analysis in seven strains of Mus musculus.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been used as a potent neurotoxin to approximate, in animals, the pathology that is observed in human Parkinson's disease. In this study, we examine the toxicity of MPTP in seven strains of mice, spanning a genetic continuum of Mus musculus as a prelude to uncovering complex traits associated with MPTP toxicity. Seven days following injection of 80 mg/kg MPTP (4x20 mg/kg every 2 h), we find that the individual mouse strains exhibit dramatic differences in SNpc neuron survival, ranging from 63% cell loss in C57BL/6J mice to 14% cell loss in Swiss-Webster (SW) mice. In order to determine if the susceptibility trait was dominant, additive or recessive, we crossed C57Bl/6J mice with either SWR/J or AKR/J mice and examined the effect of MPTP on F1 C57BL/6JxSWR/J or F1 C57BL/6JxAKR/J animals. We find that all of the F1 animals were phenotypically identical to the C57BL/6J animals. In addition, no gender differences were noted in any of the MPTP-treated inbred mice or in the F1 animals. These results suggest that susceptibility to cell loss following MPTP is autosomal dominant and this polymorphism is carried on the C57BL/6J allele.
D000818:Animals; D001479:Basal Ganglia / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D002452:Cell Count; D004198:Disease Susceptibility; D015259:Dopamine Agents / Q000633:toxicity*; D005260:Female; D005799:Genes, Dominant; D020267:MPTP Poisoning; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000235:genetics*; D012737:Sex Factors; D013045:Species Specificity; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis