Uncoupling protein 2 protects dopaminergic neurons from acute 1,2,3,6‐methyl‐phenyl‐tetrahydropyridine toxicity

Oxidative stress is implicated in the death of dopaminergic neurons in sporadic forms of Parkinson's disease. Because oxidative stress can be modulated endogenously by uncoupling proteins (UCPs), we hypothesized that specific neuronal expression of UCP2, one member of the UCP family that is rapidly induced in the CNS following insults, could confer neuroprotection in a mouse model of Parkinson's disease. We generated transgenic mice overexpressing UCP2 in catecholaminergic neurons under the control of the tyrosine hydroxylase promoter (TH‐UCP2). In these mice, dopaminergic neurons of the substantia nigra showed a twofold elevation in UCP2 expression, elevated uncoupling of their mitochondria, and a marked reduction in indicators of oxidative stress, an effect also observed in the striatum. Upon acute exposure to 1,2,3,6‐methyl‐phenyl‐tetrahydropyridine, TH‐UCP2 mice showed neuroprotection and retention of locomotor functions. Our data suggest that UCP2 may represent a drug target for slowing the progression of Parkinson's disease.

[1]  R. Roth,et al.  Coenzyme Q induces nigral mitochondrial uncoupling and prevents dopamine cell loss in a primate model of Parkinson's disease. , 2003, Endocrinology.

[2]  D. Sanchís,et al.  Distribution of the uncoupling protein 2 mRNA in the mouse brain , 1998, The Journal of comparative neurology.

[3]  Olaf Riess,et al.  AlaSOPro mutation in the gene encoding α-synuclein in Parkinson's disease , 1998, Nature Genetics.

[4]  B. Volpe,et al.  Histological and temporal characteristics of nigral transneuronal degeneration after striatal injury , 1998, Brain Research.

[5]  R J Miller,et al.  The selective toxicity of 1-methyl-4-phenylpyridinium to dopaminergic neurons: the role of mitochondrial complex I and reactive oxygen species revisited. , 2000, Molecular pharmacology.

[6]  M. Beal,et al.  Creatine and Cyclocreatine Attenuate MPTP Neurotoxicity , 1998, Experimental Neurology.

[7]  T M CARPENTER,et al.  Energy metabolism. , 1946, Annual review of physiology.

[8]  M. Vila,et al.  MPTP as a Mitochondrial Neurotoxic Model of Parkinson's Disease , 2004, Journal of bioenergetics and biomembranes.

[9]  Todd B. Sherer,et al.  Mechanism of Toxicity in Rotenone Models of Parkinson's Disease , 2003, The Journal of Neuroscience.

[10]  J. Hughes.  Selective Toxicity , 1969, The Yale Journal of Biology and Medicine.

[11]  Y. Kaneda,et al.  Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage , 2000, Nature.

[12]  Houeto Jean-Luc.  [Parkinson's disease]. , 2022, La Revue du praticien.

[13]  G. Tomasevic,et al.  Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma , 2003, Nature Medicine.

[14]  Robert L. Nussbaum,et al.  Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease , 1997 .

[15]  C. Olanow.  A radical hypothesis for neurodegeneration , 1993, Trends in Neurosciences.

[16]  K. O’Malley,et al.  The Parkinsonism-inducing Drug 1-Methyl-4-phenylpyridinium Triggers Intracellular Dopamine Oxidation , 2000, The Journal of Biological Chemistry.

[17]  Joseph P Huston,et al.  Behavioral phenotyping of the MPTP mouse model of Parkinson's disease , 2001, Behavioural Brain Research.

[18]  T. Joh,et al.  A Transgenic Mouse Model to Study Transsynaptic Regulation of Tyrosine Hydroxylase Gene Expression , 1996, Journal of neurochemistry.

[19]  Robin A. J. Smith,et al.  Superoxide Activates Mitochondrial Uncoupling Protein 2 from the Matrix Side , 2002, The Journal of Biological Chemistry.

[20]  T. Joh,et al.  Neurons of the superior nucleus of the medial habenula and ependymal cells express IL-18 in rat CNS , 2002, Brain Research.

[21]  Bruce M. Spiegelman,et al.  Towards a molecular understanding of adaptive thermogenesis , 2000, Nature.

[22]  S E Ide,et al.  Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. , 1997, Science.

[23]  K. Tipton,et al.  Advances in Our Understanding of the Mechanisms of the Neurotoxicity of MPTP and Related Compounds , 1993, Journal of neurochemistry.

[24]  C. Olanow,et al.  Oxidative stress and the pathogenesis of Parkinson's disease , 1996, Neurology.

[25]  E. Hirsch,et al.  Protective action of the peroxisome proliferator‐activated receptor‐γ agonist pioglitazone in a mouse model of Parkinson's disease , 2002, Journal of neurochemistry.

[26]  P. Rojas,et al.  Increased striatal lipid peroxidation after intracerebroventricular MPP+ administration to mice. , 1993, Pharmacology & toxicology.

[27]  B. Halliwell,et al.  The importance of free radicals and catalytic metal ions in human diseases. , 1985, Molecular aspects of medicine.

[28]  B. Volpe,et al.  Brain-derived neurotrophic factor prevents the loss of nigral neurons induced by excitotoxic striatal-pallidal lesions , 1998, Neuroscience.

[29]  M. Seldin,et al.  BMCP1, a Novel Mitochondrial Carrier with High Expression in the Central Nervous System of Humans and Rodents, and Respiration Uncoupling Activity in Recombinant Yeast* , 1998, The Journal of Biological Chemistry.

[30]  Christophe Fleury,et al.  Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia , 1997, Nature Genetics.

[31]  J. Jankovic,et al.  Pramipexole inhibits lipid peroxidation and reduces injury in the substantia nigra induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in C57BL/6 mice , 2000, Neuroscience Letters.

[32]  P. Maher,et al.  The Regulation of Reactive Oxygen Species Production during Programmed Cell Death , 1998, The Journal of cell biology.

[33]  D. D. Di Monte.  The environment and Parkinson's disease: is the nigrostriatal system preferentially targeted by neurotoxins? , 2003, The Lancet. Neurology.

[34]  J. B. Hutchins,et al.  Mitochondrial Manganese Superoxide Dismutase Prevents Neural Apoptosis and Reduces Ischemic Brain Injury: Suppression of Peroxynitrite Production, Lipid Peroxidation, and Mitochondrial Dysfunction , 1998, The Journal of Neuroscience.

[35]  B. Volpe,et al.  Age-related microglial activation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration in C57BL/6 mice , 2003, Brain Research.

[36]  O. Steward,et al.  Mitochondrial uncoupling protein‐2 protects the immature brain from excitotoxic neuronal death , 2003, Annals of neurology.

[37]  INTERNATIONAL SOCIETY FOR NEUROCHEMISTRY , 1976 .

[38]  M. Klingenberg,et al.  Coenzyme Q is an obligatory cofactor for uncoupling protein function , 2000, Nature.

[39]  A. Członkowska,et al.  The Inflammatory Reaction Following 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Intoxication in Mouse , 1999, Experimental Neurology.

[40]  A. Zhong,et al.  UCP4, a novel brain‐specific mitochondrial protein that reduces membrane potential in mammalian cells , 1999, FEBS letters.

[41]  V. Mootha,et al.  Energy Metabolism in Uncoupling Protein 3 Gene Knockout Mice* , 2000, The Journal of Biological Chemistry.

[42]  C. Barnstable,et al.  Uncoupling protein 2 prevents neuronal death including that occurring during seizures: a mechanism for preconditioning. , 2003, Endocrinology.

[43]  T. Horvath,et al.  Brain Uncoupling Protein 2: Uncoupled Neuronal Mitochondria Predict Thermal Synapses in Homeostatic Centers , 1999, The Journal of Neuroscience.

[44]  E. Couplan,et al.  Homologues of the uncoupling protein from brown adipose tissue (UCP1): UCP2, UCP3, BMCP1 and UCP4. , 2001, Biochimica et biophysica acta.

[45]  T. Shimokawa,et al.  In vivo effects of pioglitazone on uncoupling protein-2 and -3 mRNA levels in skeletal muscle of hyperglycemic KK mice. , 1998, Biochemical and biophysical research communications.

[46]  L. Dugan,et al.  BMCP1: a mitochondrial uncoupling protein in neurons which regulates mitochondrial function and oxidant production , 2001, Journal of neurochemistry.

[47]  B. Volpe,et al.  Prevention of Transneuronal Degeneration of Neurons in the Substantia Nigra Reticulata by Ablation of the Subthalamic Nucleus , 1996, Experimental Neurology.

[48]  H J Gundersen,et al.  Stereology: the fast lane between neuroanatomy and brain function ‐ or still only a tightrope? , 1992, Acta neurologica Scandinavica. Supplementum.

[49]  Donato A Di Monte,et al.  The environment and Parkinson's disease: is the nigrostriatal system preferentially targeted by neurotoxins? , 2003, The Lancet Neurology.

[50]  Subramanian Rajagopalan,et al.  Genetic or Pharmacological Iron Chelation Prevents MPTP-Induced Neurotoxicity In Vivo A Novel Therapy for Parkinson's Disease , 2003, Neuron.

[51]  C. Olanow.  Oxidation reactions in Parkinson's disease , 1990, Neurology.

[52]  D. Richard,et al.  Kainic acid upregulates uncoupling protein-2 mRNA expression in the mouse brain , 2003, Neuroreport.

[53]  T. Horvath,et al.  Brain mitochondrial uncoupling protein 2 (UCP2): a protective stress signal in neuronal injury. , 2002, Biochemical pharmacology.

[54]  S. Minoshima,et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism , 1998, Nature.

[55]  Richard E. Coggeshall,et al.  A consideration of neural counting methods , 1992, Trends in Neurosciences.

[56]  T. Sherer,et al.  Complex I and Parkinson's Disease , 2001, IUBMB life.

[57]  M. Beal,et al.  Coenzyme Q10 attenuates the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced loss of striatal dopamine and dopaminergic axons in aged mice , 1998, Brain Research.

[58]  Olanow Cw.  Oxidation reactions in Parkinson's disease. , 1990 .