Genomes and Genes
Environmental Toxicants and Neurodegeneration
Principal Investigator: Kim Tieu
Abstract: DESCRIPTION (provided by applicant): Our long term goal is to study the mechanism of neurodegeneration induced by environmental neurotoxicants. This proposal is submitted to investigate the active role of astrocytes in regulating the levels of environmental neurotoxic cations and hence, in modulating neurodegeneration. Based on our preliminary data we hypothesize that cations such as MPP+ (1-methyl-4-phenylpyridinium) and paraquat (PQ) are bi- directionally transported across the astrocytic plasma membrane by the organic cation transporter 3 (OCT3) and, through this mechanism, OCT3 modulates neurotoxicity. Thus, the tissue and cellular distribution of OCT3 should be critical in defining the differential regional susceptibility to cationic neurotoxins. Cations representing two different categories of environmental neurotoxicants with different toxicokinetics will be used. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a lipophillic compound that will be used to generate MPP+ inside of astrocytes. The goal is to assess how the release of MPP+ from astrocytes (v/a OCT3) into the extracellular space would subsequently induce selective death in the nigral dopaminergic neurons. PQ, a widely used cationic herbicide that has been linked to parkinsonism, will be used to assess how astrocytes affect neurodegeneration by taking up (via OCT3) and thus removing toxic cations from the extracellular space. Of note, both MPP+ and PQ also increase the outflow of the endogenous cation dopamine (DA), which is neurotoxic upon oxidation To test our hypotheses, mutant mice deficient in OCT3 and an OCT3 inhibitor will be used. In the first specific aim, we will assess how OCT3 regulates the levels of MPP+, PQ and DA by determining its uptake and reverse transport kinetics for these cations using both cell culture and animal models. In the second specific aim, we will evaluate how OCT3 modulates neurotoxicity through its bi-directional transport of MPP+ and PQ. We hypothesize that OCT3 ablation, by sequestrating MPP+ in astrocytes, attenuates dopaminergic neuronal death after MPTP treatment. Conversely, OCT3 ablation, by preventing the uptake of MPP+, PQ, and DA into astrocytes, enhances dopaminergic neuronal death after MPP+ and PQ treatments. Thus, our plan is to assess the magnitude of dopaminergic neurotoxicity in OCT3 mutant mice as well as co-culture models of astrocytes and dopaminergic neurons, treated with MPTP, MPP+ or PQ. We will also assess whether re-expression of OCT3 in astrocytes deficient in this transporter would reverse the neurotoxic effects. The proposed studies have potential to unravel a still unrecognized pathway by which different cell types in the brain interact with each other to modulate neurodegeneration induced by environmental toxicants. In addition, these studies may provide significant insights into a novel mechanism that contributes to the pattern of cell death as seen in neurodegenerative disorders such as sporadic Parkinson's disease.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT
- A guide to neurotoxic animal models of Parkinson's diseaseKim Tieu
Department of Neurology in the Center for Translational Neuromedicine, University of Rochester, Rochester, New York 14625, USA
Cold Spring Harb Perspect Med 1:a009316. 2011..And second, to provide an overview of basic technical requirements for assessing the pathology, structure, and function of the nigrostriatal pathway...
- Glutathione dysregulation and the etiology and progression of human diseasesNazzareno Ballatori
Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, USA
Biol Chem 390:191-214. 2009..The present report highlights and integrates the growing connections between imbalances in GSH homeostasis and a multitude of human diseases...
- The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathwayMei Cui
Department of Environmental Medicine, University of Rochester, Rochester, NY 14642, USA
Proc Natl Acad Sci U S A 106:8043-8. 2009..These results may have far-reaching implications for our understanding of the mechanism of cell death in a wide range of neurodegenerative diseases and may open new avenues for neuroprotective intervention...
- PINK1-dependent recruitment of Parkin to mitochondria in mitophagyCristofol Vives-Bauza
Department of Neurology, Columbia University, New York, NY 10032, USA
Proc Natl Acad Sci U S A 107:378-83. 2010..Thus by impairing this process, mutations in either Parkin or PINK1 may alter mitochondrial turnover which, in turn, may cause the accumulation of defective mitochondria and, ultimately, neurodegeneration in Parkinson's disease...
- Perturbations in mitochondrial dynamics induced by human mutant PINK1 can be rescued by the mitochondrial division inhibitor mdivi-1Mei Cui
Department of Neurology, University of Rochester School of Medicine, Rochester, New York 14642, USA
J Biol Chem 285:11740-52. 2010....
- Adenosine A1 receptors mediate local anti-nociceptive effects of acupunctureNanna Goldman
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA
Nat Neurosci 13:883-8. 2010..These observations indicate that adenosine mediates the effects of acupuncture and that interfering with adenosine metabolism may prolong the clinical benefit of acupuncture...
- Neurosteroid transport by the organic solute transporter OSTα-OSTβFang Fang
Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, New York 14642, USA
J Neurochem 115:220-33. 2010..These results demonstrate that OSTα-OSTβ is localized to steroidogenic cells of the brain and adrenal gland, and that it modulates DHEA/DHEAS homeostasis, suggesting that it may contribute to neurosteroid action...
- Astrocytes and therapeutics for Parkinson's diseasePhillip M Rappold
Department of Neurology, Center for Translational Neuromedicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
Neurotherapeutics 7:413-23. 2010..These emerging roles of astrocytes in the pathogenesis of Parkinson's disease constitute an exciting development with promising novel therapeutic targets...
- D-β-hydroxybutyrate is protective in mouse models of Huntington's diseaseSoyeon Lim
Department of Neurology in the Center for Translational Neuromedicine, University of Rochester, Rochester, New York, United States of America
PLoS ONE 6:e24620. 2011..These pre-clinical findings suggest that by simultaneously targeting the mitochondrial and the epigenetic abnormalities associated with mutant huntingtin, DβHB may be a valuable therapeutic agent for HD...
- Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3Phillip M Rappold
Department of Neurology in the Center for Translational Neuromedicine, University of Rochester, Rochester, NY 14642, USA
Proc Natl Acad Sci U S A 108:20766-71. 2011..This study provides a mechanism by which DAT and Oct3 modulate nigrostriatal damage induced by PQ(2+)/PQ(+) redox cycling...