TY - JOUR
T1 - Chromosomal loci influencing the susceptibility to the Parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
AU - Sedelis, Marco
AU - Hofele, Katja
AU - Schwarting, Rainer K.W.
AU - Huston, Joseph P.
AU - Belknap, John K.
PY - 2003/9/10
Y1 - 2003/9/10
N2 - 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.
AB - 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.
KW - Basal ganglia
KW - Dopamine
KW - F intercross
KW - Inbred strains
KW - MPTP
KW - Mouse
KW - Parkinson's disease
KW - Quantitative trait loci
UR - http://www.scopus.com/inward/record.url?scp=0141856492&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0141856492&partnerID=8YFLogxK
U2 - 10.1523/jneurosci.23-23-08247.2003
DO - 10.1523/jneurosci.23-23-08247.2003
M3 - Article
C2 - 12967986
AN - SCOPUS:0141856492
SN - 0270-6474
VL - 23
SP - 8247
EP - 8253
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 23
ER -