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Gait Analysis of Age-dependent Motor Impairments in Mice with Neurodegeneration
Published on: June 18, 2018
Transforming growth factor beta2 haploinsufficient mice develop age-related nigrostriatal dopamine deficits
Zane B Andrews1, Hua Zhao, Tony Frugier
1Neuromuscular Research Group, Department of Anatomy and Structural Biology, School of Medical Sciences, University of Otago, P.O. Box 913, Dunedin, New Zealand.
Abstract:
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.
Insights
Transforming growth factor-beta 2 (TGF-beta2) deficiency in mice leads to subtle dopaminergic neuron loss and reduced striatal dopamine. This suggests lower TGF-beta2 levels may increase Parkinson disease risk.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Transforming growth factor-betas (TGF-betas) are crucial for dopaminergic neuron development.
- Elevated TGF-beta levels are observed in cerebrospinal fluid (CSF) of Parkinson's disease (PD) patients.
- The precise role of TGF-beta2 in nigrostriatal pathway integrity and PD pathogenesis remains unclear.
Purpose of the Study:
- To investigate the impact of TGF-beta2 haploinsufficiency on dopaminergic neurons in the substantia nigra pars compacta.
- To assess the functional consequences of reduced TGF-beta2 levels on striatal dopamine.
- To explore the potential link between TGF-beta2 levels and Parkinson's disease risk.
Main Methods:
- Generation and analysis of TGF-beta2 haploinsufficient (TGF-beta2+/-) mice.
- Quantification of dopaminergic neurons in the substantia nigra pars compacta.
- Measurement of striatal dopamine and its metabolites (e.g., 3,4-dihydroxphenylacetic acid).
- Assessment of monoamine oxidase-B (MAO-B) levels and sensitivity to MPTP neurotoxin.
Main Results:
- TGF-beta2+/- mice exhibited a 12% reduction in dopaminergic neurons compared to wild-type littermates at 6 weeks.
- Striatal dopamine levels decreased to 70% of normal over 5 months in TGF-beta2+/- mice, with compensatory mechanisms maintaining dopamine stimulation.
- Monoamine oxidase-B levels were reduced in TGF-beta2+/- mice, yet they showed normal MPTP sensitivity.
Conclusions:
- Subclinical defects in dopaminergic neurons occur in TGF-beta2 haploinsufficient mice.
- Reduced TGF-beta2 levels may compromise the functional reserve of the nigrostriatal pathway.
- Naturally lower TGF-beta2 levels could represent a risk factor for developing Parkinson's disease.
