Effects of decreased dopamine transporter levels on nigrostriatal neurons and paraquat/maneb toxicity in mice

NEUROBIOLOGY OF AGING

卷:51

Article

Richter, Franziska¹  Gabby, Lauryn¹  McDowell, Kimberly A.¹  Mulligan, Caitlyn K.¹  De la Rosa, Krystal¹  Sioshansi, Pedrom C.¹  Mortazavi, Farzad¹  Cely, Ingrid²  Ackerson, Larry C.²  Tsan, Linda²  Murphy, Niall P.²  Maidment, Nigel T.²  Chesselet, Marie-Francoise¹ 

[1] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA

[2] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Hatos Ctr, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA

关键词: Parkinson's disease;    Stereology;    Animal model;    Environmental toxins;    Neurodegeneration;   

DOI  :  10.1016/j.neurobiolaging.2016.11.015

来源: Elsevier

【 摘 要 】

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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