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Dopamine transporter mRNA levels are high in midbrain neurons vulnerable to MPTP
M K Sanghera1, K Manaye, A McMahon
1Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas 75235-9070, USA.
Abstract:
The neurotoxin MPTP kills only certain midbrain dopaminergic (DA) neurons to produce a model of Parkinson's disease. The dopamine transporter (DAT) is important to MPTP toxicity because to be neurotoxic, an MPTP metabolite must first gain access to the DA neuron via the DAT. Also, MPTP is less toxic to DA neurons that contain the putative neuroprotective calcium-binding protein calbindin-D28k (CB). The present study examined the relative importance of DAT activity and CB for cellular vulnerability to MPTP-induced degeneration in the C57BL/6 mouse. Cells that were vulnerable to MPTP were found to contain high levels of DAT mRNA, whereas cells that were not vulnerable contained low levels. Also, the few substantia nigra cells remaining after a toxic dose of MPTP contained only low levels of DAT mRNA. However, there was not a strong relationship between cellular resistance to MPTP toxicity and cells containing CB. These data provide in vivo evidence for a direct correlation between midbrain cellular vulnerability to MPTP toxicity and the activity of the DAT.
Insights
MPTP neurotoxicity in Parkinson's disease models depends on dopamine transporter (DAT) activity. Vulnerable neurons show high DAT mRNA, while neuroprotective calbindin-D28k (CB) has minimal impact on MPTP toxicity.
Area of Science:
- Neuroscience
- Toxicology
- Parkinson's Disease Research
Background:
- MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxin used to model Parkinson's disease.
- MPTP toxicity selectively targets midbrain dopaminergic (DA) neurons.
- Dopamine transporter (DAT) facilitates MPTP metabolite entry into DA neurons, and calbindin-D28k (CB) may offer neuroprotection.
Purpose of the Study:
- To investigate the roles of DAT activity and CB expression in MPTP-induced DA neuron vulnerability.
- To determine the relative importance of DAT and CB in MPTP neurotoxicity in vivo.
Main Methods:
- Utilized the C57BL/6 mouse model.
- Examined MPTP neurotoxicity in relation to DAT mRNA levels and CB expression in midbrain DA neurons.
Main Results:
- Vulnerable DA neurons exhibited high DAT mRNA levels.
- Resistant DA neurons displayed low DAT mRNA levels.
- No significant correlation was found between CB expression and resistance to MPTP toxicity.
Conclusions:
- Cellular vulnerability to MPTP neurotoxicity is directly correlated with DAT activity in vivo.
- DAT expression, not CB, is the primary determinant of DA neuron susceptibility to MPTP.