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Effects of decreased dopamine transporter levels on nigrostriatal neurons and paraquat/maneb toxicity in mice.
Neurobiol Aging. 2017 03; 51:54-66.NA

Abstract

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 knock-down 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.

Authors+Show Affiliations

Department of Neurology, UCLA, Los Angeles, CA, USA. Electronic address: franziska.richter@vmf.uni-leipzig.de.Department of Neurology, UCLA, Los Angeles, CA, USA.Department of Neurology, UCLA, Los Angeles, CA, USA.Department of Neurology, UCLA, Los Angeles, CA, USA.Department of Neurology, UCLA, Los Angeles, CA, USA.Department of Neurology, UCLA, Los Angeles, CA, USA.Department of Neurology, UCLA, Los Angeles, CA, USA.Hatos Center, Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, USA.Hatos Center, Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, USA.Hatos Center, Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, USA.Hatos Center, Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, USA.Hatos Center, Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, USA.Department of Neurology, UCLA, Los Angeles, CA, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

28038352

Citation

Richter, Franziska, et al. "Effects of Decreased Dopamine Transporter Levels On Nigrostriatal Neurons and Paraquat/maneb Toxicity in Mice." Neurobiology of Aging, vol. 51, 2017, pp. 54-66.
Richter F, Gabby L, McDowell KA, et al. Effects of decreased dopamine transporter levels on nigrostriatal neurons and paraquat/maneb toxicity in mice. Neurobiol Aging. 2017;51:54-66.
Richter, F., Gabby, L., McDowell, K. A., Mulligan, C. K., De La Rosa, K., Sioshansi, P. C., Mortazavi, F., Cely, I., Ackerson, L. C., Tsan, L., Murphy, N. P., Maidment, N. T., & Chesselet, M. F. (2017). Effects of decreased dopamine transporter levels on nigrostriatal neurons and paraquat/maneb toxicity in mice. Neurobiology of Aging, 51, 54-66. https://doi.org/10.1016/j.neurobiolaging.2016.11.015
Richter F, et al. Effects of Decreased Dopamine Transporter Levels On Nigrostriatal Neurons and Paraquat/maneb Toxicity in Mice. Neurobiol Aging. 2017;51:54-66. PubMed PMID: 28038352.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of decreased dopamine transporter levels on nigrostriatal neurons and paraquat/maneb toxicity in mice. AU - Richter,Franziska, AU - Gabby,Lauryn, AU - McDowell,Kimberly A, AU - Mulligan,Caitlyn K, AU - De La Rosa,Krystal, AU - Sioshansi,Pedrom C, AU - Mortazavi,Farzad, AU - Cely,Ingrid, AU - Ackerson,Larry C, AU - Tsan,Linda, AU - Murphy,Niall P, AU - Maidment,Nigel T, AU - Chesselet,Marie-Françoise, Y1 - 2016/12/01/ PY - 2016/04/04/received PY - 2016/11/16/revised PY - 2016/11/17/accepted PY - 2016/12/31/pubmed PY - 2017/9/29/medline PY - 2016/12/31/entrez KW - Animal model KW - Environmental toxins KW - Neurodegeneration KW - Parkinson's disease KW - Stereology SP - 54 EP - 66 JF - Neurobiology of aging JO - Neurobiol Aging VL - 51 N2 - 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 knock-down 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. SN - 1558-1497 UR - https://www.unboundmedicine.com/medline/citation/28038352/Effects_of_decreased_dopamine_transporter_levels_on_nigrostriatal_neurons_and_paraquat/maneb_toxicity_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0197-4580(16)30302-5 DB - PRIME DP - Unbound Medicine ER -