Journal
NEUROBIOLOGY OF AGING
Volume 51, Issue -, Pages 54-66Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2016.11.015
Keywords
Parkinson's disease; Stereology; Animal model; Environmental toxins; Neurodegeneration
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Funding
- NIEHS [P01-ES016732]
- American Parkinson Disease Association Center for Advanced Research at UCLA
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How genetic variations in the dopamine transporter (DAT) combined with exposure to environmental toxins modulate the risk of Parkinson's disease remains unclear. Using unbiased stereology in DAT knockdown mice (DAT-KD) and wild-type (WT) littermates, we found that decreased DAT caused a loss of tyrosine hydroxylase-positive (dopaminergic) neurons in subregions of the substantia nigra pars compacta at 3-4 days, 5 weeks, and 18 months of age. Both genotypes lost dopaminergic neurons with age and remaining neurons at 11 months were resilient to paraquat/maneb. In 5-week-old mice, the toxins decreased substantia nigra pars compacta dopaminergic neurons in both genotypes but less in DAT-KD. Regional analysis revealed striking differences in the subsets of neurons affected by low DAT, paraquat/maneb, and aging. In particular, we show that a potentially protective effect of low DAT against toxin exposure is not sufficient to reduce death of all nigrostriatal dopaminergic neurons. Thus, different regional vulnerability of nigrostriatal dopaminergic neurons may contribute to an increased risk of developing Parkinson's disease when multiple factors are combined. (C) 2016 Elsevier Inc. All rights reserved.
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