title: Effects of decreased dopamine transporter levels on nigrostriatal neurons and paraquat/maneb toxicity in mice.
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.affiliation: Department of Neurology, UCLA, Los Angeles, CA, USA. Electronic address: franziska.richter@vmf.uni-leipzig.de.
authors.forename: Franziska
authors.initials: F
authors.lastname: Richter
authors.affiliation: Department of Neurology, UCLA, Los Angeles, CA, USA.
authors.forename: Lauryn
authors.initials: L
authors.lastname: Gabby
authors.affiliation: Department of Neurology, UCLA, Los Angeles, CA, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: McDowell
authors.affiliation: Department of Neurology, UCLA, Los Angeles, CA, USA.
authors.forename: Caitlyn K
authors.initials: CK
authors.lastname: Mulligan
authors.affiliation: Department of Neurology, UCLA, Los Angeles, CA, USA.
authors.forename: Krystal
authors.initials: K
authors.lastname: De La Rosa
authors.affiliation: Department of Neurology, UCLA, Los Angeles, CA, USA.
authors.forename: Pedrom C
authors.initials: PC
authors.lastname: Sioshansi
authors.affiliation: Department of Neurology, UCLA, Los Angeles, CA, USA.
authors.forename: Farzad
authors.initials: F
authors.lastname: Mortazavi
authors.affiliation: Hatos Center, Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, USA.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Cely
authors.affiliation: Hatos Center, Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, USA.
authors.forename: Larry C
authors.initials: LC
authors.lastname: Ackerson
authors.affiliation: Hatos Center, Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Tsan
authors.affiliation: Hatos Center, Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, USA.
authors.forename: Niall P
authors.initials: NP
authors.lastname: Murphy
authors.affiliation: Hatos Center, Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, USA.
authors.forename: Nigel T
authors.initials: NT
authors.lastname: Maidment
authors.affiliation: Department of Neurology, UCLA, Los Angeles, CA, USA.
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Chesselet
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics*; D059290:Dopaminergic Neurons / Q000473:pathology*; D014644:Genetic Variation; D008297:Male; D008344:Maneb / Q000633:toxicity*; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010269:Paraquat / Q000633:toxicity*; D010300:Parkinson Disease / Q000209:etiology*; D065842:Pars Compacta / Q000473:pathology*; D012306:Risk
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D008344:Maneb; D010269:Paraquat
keywords: Animal model; Environmental toxins; Neurodegeneration; Parkinson's disease; Stereology