Transforming growth factor beta2 haploinsufficient mice develop age-related nigrostriatal dopamine deficits.
The transforming growth factor-betas (TGF-betas) regulate the induction of dopaminergic neurons and are elevated in the CSF of Parkinson's patients. We report here that mice with TGF-beta2 haploinsufficiency (TGF-beta2+/-) have subclinical defects in the dopaminergic neurons of their substantia nigra pars compacta. At 6 weeks of age, the TGF-beta2+/- mice had 12% fewer dopaminergic neurons than wild-type littermates. No additional loss of neurons occurred during the next 5 months, although striatal dopamine declined to 70% of normal. The level of 3,4-dihydroxphenylacetic acid was normal in the TGF-beta2+/- mice, indicating that a compensatory mechanism maintains dopamine stimulation of their striatum. The TGF-beta2+/- mice had normal sensitivity to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, despite having reduced levels of monoamine oxidase-B. These results raise the possibility that people with naturally low levels of TGF-beta2 may have less functional reserve in their nigrostriatal pathway, causing them to be at increased risk of developing Parkinson disease.
Andrews
Zane B
ZB
Neuromuscular Research Group, Department of Anatomy and Structural Biology, School of Medical Sciences, University of Otago, P.O. Box 913, Dunedin, New Zealand.
Zhao
Hua
H
Frugier
Tony
T
Meguro
Reiko
R
Grattan
David R
DR
Koishi
Kyoko
K
McLennan
Ian S
IS
D000367:Age Factors; D000818:Animals; D002452:Cell Count; D004298:Dopamine / Q000378:metabolism*; D006239:Haplotypes; D007150:Immunohistochemistry; D020267:MPTP Poisoning / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics*; D053781:Transforming Growth Factor beta2
D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D004298:Dopamine