Sensitivity to MPTP is not increased in Parkinson's disease-associated mutant alpha-synuclein transgenic mice.
Environmental and genetic factors that contribute to the pathogenesis of Parkinson's disease are discussed. Mutations in the alpha-synuclein (alphaSYN ) gene are associated with rare cases of autosomal-dominant Parkinson's disease. We have analysed the dopaminergic system in transgenic mouse lines that expressed mutant [A30P]alphaSYN under the control of a neurone-specific Thy-1 or a tyrosine hydroxylase (TH) promoter. The latter mice showed somal and neuritic accumulation of transgenic [A30P]alphaSYN in TH-positive neurones in the substantia nigra. However, there was no difference in the number of TH-positive neurones in the substantia nigra and the concentrations of catecholamines in the striatum between these transgenic mice and non-transgenic littermates. To investigate whether forced expression of [A30P]alphaSYN increased the sensitivity to putative environmental factors we subjected transgenic mice to a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) regimen. The MPTP-induced decrease in the number of TH-positive neurones in the substantia nigra and the concentrations of catecholamines in the striatum did not differ in any of the [A30P]alphaSYN transgenic mouse lines compared with wild-type controls. These results suggest that mutations and forced expression of alphaSYN are not likely to increase the susceptibility to environmental toxins in vivo.
Rathke-Hartlieb
S
S
Neurodegeneration Laboratory, Department of Neurology, University of Tübingen, Tübingen, Germany.
Kahle
P J
PJ
Neumann
M
M
Ozmen
L
L
Haid
S
S
Okochi
M
M
Haass
C
C
Schulz
J B
JB
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology; D016501:Neurites / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D013378:Substantia Nigra / Q000378:metabolism; D051843:Synucleins; D018800:Thy-1 Antigens / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D018800:Thy-1 Antigens; D051844:alpha-Synuclein; D015102:3,4-Dihydroxyphenylacetic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D006719:Homovanillic Acid