Smeyne: Genes that regulate sensitivity to the Parkinsonian drug MPTP

My lab is interested in the identification of genes that regulate sensitivity to the Parkinsonian drug MPTP.  Parkinson’s disease is a debilitating neurologic disorder that is characterized by a loss of pigmented neurons in the substantia nigra pars compacta (SNpc) and is probably caused by a multifactorial process involving an interaction of gene effects, subject age, and exposure to an environmental insult. To create our animal model of Parkinson’s disease, we used the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Having found that the C57Bl/6J and SWR/J strains of mice differ in sensitivity to MPTP, we are examining the gene(s) that underlie the genetic susceptibility to MPTP using Quantitative Trait Loci (QTL) Analysis.  Following an examination of 58 animals using 120 DNA markers, we have identified 4 putative QTL’s.  We are now in the process of examining the genetic code in these regions to uncover the specific genes responsible for MPTP susceptibility.  Our lab is also studying which cells (neurons and/or glia) are responsible for the toxicity seen following MPTP administration.  Using a novel chimeric culture method, we have found that the genotype of the glial cell plays a crucial role in determining whether an SNpc cell will die after exposure to MPTP. This finding may have implications for the development of novel therapies for the treatment of Parkinson’s disease.


Last update: April 2003