Environmental Toxicants and Neurodegeneration

Summary

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

Top Publications

  1. pmc A guide to neurotoxic animal models of Parkinson's disease
    Kim 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
  2. pmc Glutathione dysregulation and the etiology and progression of human diseases
    Nazzareno Ballatori
    Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, USA
    Biol Chem 390:191-214. 2009
  3. pmc The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway
    Mei Cui
    Department of Environmental Medicine, University of Rochester, Rochester, NY 14642, USA
    Proc Natl Acad Sci U S A 106:8043-8. 2009
  4. pmc PINK1-dependent recruitment of Parkin to mitochondria in mitophagy
    Cristofol Vives-Bauza
    Department of Neurology, Columbia University, New York, NY 10032, USA
    Proc Natl Acad Sci U S A 107:378-83. 2010
  5. pmc Perturbations in mitochondrial dynamics induced by human mutant PINK1 can be rescued by the mitochondrial division inhibitor mdivi-1
    Mei Cui
    Department of Neurology, University of Rochester School of Medicine, Rochester, New York 14642, USA
    J Biol Chem 285:11740-52. 2010
  6. pmc Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture
    Nanna Goldman
    Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA
    Nat Neurosci 13:883-8. 2010
  7. pmc Neurosteroid transport by the organic solute transporter OSTα-OSTβ
    Fang Fang
    Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, New York 14642, USA
    J Neurochem 115:220-33. 2010
  8. pmc Astrocytes and therapeutics for Parkinson's disease
    Phillip 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
  9. pmc D-β-hydroxybutyrate is protective in mouse models of Huntington's disease
    Soyeon 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
  10. pmc Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3
    Phillip 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

Scientific Experts

  • Kim Tieu
  • NED BALLATORI
  • Mei Cui
  • Phillip M Rappold
  • Serge Przedborski
  • Whitney V Christian
  • Adrianne S Chesser
  • Jonathan C Grima
  • Soyeon Lim
  • Jonathan A Javitch
  • Fang Fang
  • Nanna Goldman
  • Cristofol Vives-Bauza
  • Lihua Duan
  • Namita Sen
  • David Blum
  • Jacqueline Tibbett
  • Ted M Dawson
  • Sadie G Gorman
  • Michael Chen
  • Jiang Fan Chen
  • Qiwu Xu
  • Takumi Fujita
  • Jessica May
  • Wencheng Liu
  • Valina L Dawson
  • Jordi Magrane
  • Chenjian Li
  • Lane Bekar
  • Han Seok Ko
  • Jurgen Schnermann
  • Yisang Yoon
  • Fushun Wang
  • Tina K Jensen
  • Wei Liu
  • Rosa L A de Vries
  • Chun Zhou
  • Yong Pei
  • Maja Aleksandra Tocilescu
  • Darren J Moore
  • Jiaoti Huang
  • Yong Huang
  • Takahiro Takano
  • Xiangna Tang
  • Weiguo Peng
  • Jiho Kim
  • Xiaoning Han
  • Maiken Nedergaard
  • Regis Grailhe
  • Radha Aras
  • Mamata Hatwar
  • Vernice Jackson-Lewis
  • Joseph Panza

Detail Information

Publications11

  1. pmc A guide to neurotoxic animal models of Parkinson's disease
    Kim 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...
  2. pmc Glutathione dysregulation and the etiology and progression of human diseases
    Nazzareno 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...
  3. pmc The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway
    Mei 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...
  4. pmc PINK1-dependent recruitment of Parkin to mitochondria in mitophagy
    Cristofol 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...
  5. pmc Perturbations in mitochondrial dynamics induced by human mutant PINK1 can be rescued by the mitochondrial division inhibitor mdivi-1
    Mei Cui
    Department of Neurology, University of Rochester School of Medicine, Rochester, New York 14642, USA
    J Biol Chem 285:11740-52. 2010
    ....
  6. pmc Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture
    Nanna 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...
  7. pmc Neurosteroid transport by the organic solute transporter OSTα-OSTβ
    Fang 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...
  8. pmc Astrocytes and therapeutics for Parkinson's disease
    Phillip 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...
  9. pmc D-β-hydroxybutyrate is protective in mouse models of Huntington's disease
    Soyeon 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...
  10. pmc Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3
    Phillip 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...