Systems analysis of genetic variation in MPTP neurotoxicity in mice

Neurotoxicology. 2013 Jul;37:26-34. doi: 10.1016/j.neuro.2013.03.010. Epub 2013 Apr 1.


We analyzed genetic variation in severity of neuronal damage using the known dopaminergic neurotoxicant, MPTP, as a prototypical chemical denervation agent. Male mice from ten members of the BXD family of recombinant inbred strains received 12.5 mg/kg MPTP s.c. (vs. saline) and 48 h later brains were taken for multiple related biochemical analyses. Striatal dopamine (DA) and its metabolites, DOPAC and HVA, and serotonin and its metabolite, 5-HIAAA, were analyzed by HPLC. DA turnover was assessed using DOPAC/DA and HVA/DA ratios. Striatal tyrosine hydroxylase (TH), glial fibrilary acidic protein (GFAP), and iron content in ventral midbrain were quantified. All dopamine measures, as well as TH and GFAP, demonstrated wide, genotype-dependent differences in response to MPTP. Serotonin was largely unaffected. Principal components analysis (PC) on difference values, saline minus MPTP, for DA, DOPAC, HVA, and TH, yielded a dominant principal component. The PC trait residuals for each genotype were compared against complementary expression data for striatum of the same strains. Three transcripts representing Mtap2, Lancl 1, and Kansl1l were highly correlated with the PC, as was the difference score, MPTP minus saline for GFAP. This systems approach to the study of environmental neurotoxicants holds promise to define individual genetic differences that contribute to variability in susceptibility to risk factors for diseases such as Parkinson's disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3,4-Dihydroxyphenylacetic Acid / metabolism
  • Animals
  • Biomarkers / metabolism
  • Brain / drug effects*
  • Brain / metabolism
  • Disease Models, Animal
  • Dopamine / metabolism
  • Gene Expression Regulation
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Genomics
  • Glial Fibrillary Acidic Protein / metabolism
  • Homovanillic Acid / metabolism
  • Hydroxyindoleacetic Acid / metabolism
  • Iron / metabolism
  • MPTP Poisoning / genetics*
  • MPTP Poisoning / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Multivariate Analysis
  • Phenotype
  • Principal Component Analysis
  • Risk Factors
  • Serotonin / metabolism
  • Species Specificity
  • Systems Biology*
  • Tyrosine 3-Monooxygenase / metabolism


  • Biomarkers
  • Glial Fibrillary Acidic Protein
  • 3,4-Dihydroxyphenylacetic Acid
  • Serotonin
  • Hydroxyindoleacetic Acid
  • Iron
  • Tyrosine 3-Monooxygenase
  • Dopamine
  • Homovanillic Acid