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The Journal of Neuroscience, September 10, 2003, 23(23):8247-8253

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Chromosomal Loci Influencing the Susceptibility to the Parkinsonian Neurotoxin 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine

Marco Sedelis,1 Katja Hofele,2 Rainer K. W. Schwarting,3 Joseph P. Huston,1 and John K. Belknap4

1Institute of Physiological Psychology I, and Center for Biological and Medical Research, Heinrich-Heine-University of Düsseldorf, 40225 Düsseldorf, Germany, 2Nervous System Research, Novartis Pharma AG, 4002 Basel, Switzerland, 3Experimental and Physiological Psychology, Philipps-University of Marburg, 35032 Marburg, Germany, and 4Research Service (R&D-5), Veterans Affairs Medical Center, and Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon 97239

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the dysfunction of the nigrostriatal dopaminergic pathway. Although its etiology is not yet fully understood, an interaction of genetic predisposition and environmental factors is frequently discussed. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can evoke PD-like symptoms and neuropathological changes in various species, including mice. It was found repeatedly that mouse strains differ in their susceptibility to MPTP, which might serve as a model for genetic predisposition to neurodegeneration of the nigrostriatal system. In the present study, F2 intercross mice, derived from parental strains with high (C57BL/6J) versus low (BALB/cJ) MPTP susceptibility, were treated with MPTP and phenotyped for dopamine (DA) loss in the neostriatum, a highly sensitive marker of nigrostriatal dysfunction. A subsequent quantitative trait loci analysis revealed a gender-dependent locus for DA loss on chromosome 15 and a putative locus on chromosome 13. A number of potential candidate genes, including the membrane dopamine transporter, are located in the respective areas. Several mechanisms that are possibly involved in the control of the action of MPTP on the nigrostriatal system are discussed.

Key words: MPTP; quantitative trait loci; Parkinson's disease; dopamine; basal ganglia; F2 intercross; inbred strains; mouse

Received May 15, 2003; revised July 7, 2003; accepted July 11, 2003.






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