Enhanced substantia nigra mitochondrial pathology in human α-synuclein transgenic mice after treatment with MPTP 1 1 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Recent studies have implicated alpha-synuclein (alpha-S) in the pathogenesis of Parkinson's disease (PD). The mechanisms underlying PD are not completely understood; however, mitochondrial complex I inhibition and oxidative injury may be involved. Because the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent complex I inhibitor that can cause oxidative injury and mimic many aspects of PD in treated animals, we sought to determine whether the overexpression of alpha-S in transgenic (tg) mice (alpha-S-tg) would enhance the substantia nigra (SN) pathology resulting from treatment with MPTP. For this purpose, alpha-S-tg mice were produced expressing high levels of wild-type (wt) human alpha-S under the control of the neuron-specific Thy-1 promoter. Alpha-S-tg mice and non-tg controls were treated with MPTP (15 mg/kg ip, twice a week for 2 weeks) or saline (Sal) and then examined 2 weeks after completion of treatment by transmission electron microscopy (EM). We found that alpha-S-tg mice treated with MPTP had extensive mitochondrial alterations, increases in mitochondrial size, filamentous neuritic aggregations, axonal degeneration, and formation of electron dense perinuclear cytoplasmic inclusions in the SN that did not occur in the hippocampus or neocortex, nor in MPTP-treated non-tg mice or Sal-treated alpha-S-tg mice. These findings support the potential involvement of alpha-S expression in the vulnerability of SN neurons to toxicity from mitochondrial complex I inhibitors and the subsequent development of neurodegenerative pathology.

[1]  S. Kato,et al.  Neuropathological study on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine of the crab-eating monkey , 2004, Acta Neuropathologica.

[2]  Howard J. Federoff,et al.  Behavioral and Neurochemical Effects of Wild-Type and Mutated Human α-Synuclein in Transgenic Mice , 2002, Experimental Neurology.

[3]  E. Masliah,et al.  Abnormal distribution of the non-Abeta component of Alzheimer's disease amyloid precursor/alpha-synuclein in Lewy body disease as revealed by proteinase K and formic acid pretreatment. , 1998, Laboratory investigation; a journal of technical methods and pathology.

[4]  L. Forno.  Neuropathologic Features of Parkinson's, Huntington's, and Alzheimer's Diseases a , 1992, Annals of the New York Academy of Sciences.

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

[6]  Pico Caroni,et al.  Neuropathology in Mice Expressing Human α-Synuclein , 2000, The Journal of Neuroscience.

[7]  E. Masliah,et al.  Role of Cytochrome c as a Stimulator of α-Synuclein Aggregation in Lewy Body Disease* , 1999, The Journal of Biological Chemistry.

[8]  P. Riederer,et al.  Animal models of Parkinson's disease: An empirical comparison with the phenomenology of the disease in man , 2005, Journal of Neural Transmission.

[9]  Makoto Hashimoto,et al.  Differential neuropathological alterations in transgenic mice expressing α‐synuclein from the platelet‐derived growth factor and Thy‐1 promoters , 2002, Journal of neuroscience research.

[10]  J. Trojanowski,et al.  Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. , 2000, Science.

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

[12]  C. Marsden,et al.  Basal Lipid Peroxidation in Substantia Nigra Is Increased in Parkinson's Disease , 1989, Journal of neurochemistry.

[13]  L. Mucke,et al.  Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. , 2000, Science.

[14]  P. Lansbury,et al.  Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson's disease: implications for pathogenesis and therapy. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[15]  M. Caron,et al.  Dopamine transporter expression confers cytotoxicity to low doses of the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[16]  P. Blumbergs,et al.  In Situ and in Vitro Study of Colocalization and Segregation of α-Synuclein, Ubiquitin, and Lipids in Lewy Bodies , 2000, Experimental Neurology.

[17]  M. Goedert,et al.  Binding of α-Synuclein to Brain Vesicles Is Abolished by Familial Parkinson’s Disease Mutation* , 1998, The Journal of Biological Chemistry.

[18]  John Hardy,et al.  The A53T α-Synuclein Mutation Increases Iron-Dependent Aggregation and Toxicity , 2000, The Journal of Neuroscience.

[19]  M. Mattson,et al.  “Apoptotic” biochemical cascades in synaptic compartments: Roles in adaptive plasticity and neurodegenerative disorders , 1999, Journal of neuroscience research.

[20]  R. Elble.  Animal Models of Action Tremor , 2008, Movement disorders : official journal of the Movement Disorder Society.

[21]  J. Luthman,et al.  Time course of MPTP-induced degeneration of the nigrostriatal dopamine system in C57 BL/6 mice , 1988, Brain Research Bulletin.

[22]  C. Marsden,et al.  Mitochondrial Complex I Deficiency in Parkinson's Disease , 1990, Lancet.

[23]  Rebecca A. Betensky,et al.  α-Synuclein occurs in lipid-rich high molecular weight complexes, binds fatty acids, and shows homology to the fatty acid-binding proteins , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[24]  P. Sonsalla,et al.  The influence of dose and dosing interval on MPTP-induced dopaminergic neurotoxicity in mice. , 1986, European journal of pharmacology.

[25]  L. Wolman,et al.  Ultrastructural observations in Parkinsonism , 1969, The Journal of pathology.

[26]  A. Goldberg,et al.  PAN, the proteasome-activating nucleotidase from archaebacteria, is a protein-unfolding molecular chaperone , 2000, Nature Cell Biology.

[27]  S. Pennathur,et al.  Mass Spectrometric Quantification of 3-Nitrotyrosine, ortho-Tyrosine, and o,o′-Dityrosine in Brain Tissue of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated Mice, a Model of Oxidative Stress in Parkinson's Disease* , 1999, The Journal of Biological Chemistry.

[28]  R. Burke,et al.  Time course and morphology of dopaminergic neuronal death caused by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. , 1995, Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration.

[29]  Hitoshi Takahashi,et al.  NACP, a presynaptic protein, immunoreactivity in Lewy bodies in Parkinson's disease , 1997, Neuroscience Letters.

[30]  S. Shin,et al.  Formation and Removal of α-Synuclein Aggregates in Cells Exposed to Mitochondrial Inhibitors* , 2002, The Journal of Biological Chemistry.

[31]  D. Cory-Slechta,et al.  Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss , 1999, Brain Research.

[32]  Seung-Jae Lee,et al.  Characterization of cytoplasmic alpha-synuclein aggregates. Fibril formation is tightly linked to the inclusion-forming process in cells. , 2002, The Journal of biological chemistry.

[33]  J. Glowinski,et al.  Dendritic release of dopamine in the substantia nigra , 1981, Nature.

[34]  Seung-Jae Lee,et al.  Membrane-bound α-Synuclein Has a High Aggregation Propensity and the Ability to Seed the Aggregation of the Cytosolic Form* , 2002, The Journal of Biological Chemistry.

[35]  Y. Agid,et al.  Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease. , 1997, Histology and histopathology.

[36]  V. Uversky,et al.  The Herbicide Paraquat Causes Up-regulation and Aggregation of α-Synuclein in Mice , 2002, The Journal of Biological Chemistry.

[37]  J. Langston,et al.  An electron microscopic study of MPTP-induced inclusion bodies in an old monkey , 1988, Brain Research.

[38]  A. Parent,et al.  The Nigrostriatal Pathway in the Rat: A Single-Axon Study of the Relationship between Dorsal and Ventral Tier Nigral Neurons and the Striosome/Matrix Striatal Compartments , 2001, The Journal of Neuroscience.

[39]  Robert Burke,et al.  Resistance of α-synuclein null mice to the parkinsonian neurotoxin MPTP , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[40]  Smita Patel,et al.  Golgi Fragmentation Occurs in the Cells with Prefibrillar α-Synuclein Aggregates and Precedes the Formation of Fibrillar Inclusion* , 2002, The Journal of Biological Chemistry.

[41]  D. Maraganore.  Epidemiology and Genetics of Parkinson’s Disease , 2000 .

[42]  Robert Hill,et al.  Low platelet mitochondrial complex I and complex II/III activity in early untreated parkinson's disease , 1995, Annals of neurology.

[43]  E. Masliah,et al.  Oxidative stress induces amyloid-like aggregate formation of NACP/α-synuclein in vitro , 1999 .

[44]  Virginia M. Y. Lee,et al.  Oxidative post‐translational modifications of α‐synuclein in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of Parkinson's disease , 2001, Journal of neurochemistry.

[45]  M. Kuhar,et al.  The dopamine transporter is localized to dendritic and axonal plasma membranes of nigrostriatal dopaminergic neurons , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[46]  M. Mattson,et al.  Prostate Apoptosis Response‐4 Production in Synaptic Compartments Following Apoptotic and Excitotoxic Insults , 1999, Journal of neurochemistry.

[47]  P. Clarke,et al.  Developmental cell death: morphological diversity and multiple mechanisms , 2004, Anatomy and Embryology.

[48]  P. Lansbury,et al.  Annular alpha-synuclein protofibrils are produced when spherical protofibrils are incubated in solution or bound to brain-derived membranes. , 2002, Biochemistry.

[49]  J. Langston,et al.  Environmental Risk Factors and Parkinson's Disease: Selective Degeneration of Nigral Dopaminergic Neurons Caused by the Herbicide Paraquat , 2002, Neurobiology of Disease.

[50]  J. Penney,et al.  Glutamate Receptor Binding Sites in MPTP-Treated Mice , 1993, Experimental Neurology.

[51]  W. Bender,et al.  A Drosophila model of Parkinson's disease , 2000, Nature.

[52]  C. Plata-salamán,et al.  Abnormal patterns of microtubule-associated protein-2 (MAP-2) immunolabeling in neuronal nuclei and Lewy bodies in Parkinson's disease substantia nigra brain tissues , 2001, Neuroscience Letters.

[53]  E. Masliah,et al.  α-Synuclein Promotes Mitochondrial Deficit and Oxidative Stress , 2000 .

[54]  Todd B. Sherer,et al.  Chronic systemic pesticide exposure reproduces features of Parkinson's disease , 2000, Nature Neuroscience.

[55]  V. Tennyson,et al.  Phase and Electron Microscopic Observations of Lewy Bodies and Melanin Granules in the Substantia Nigra and Locus Caeruleus in Parkinson's Disease , 1965 .

[56]  R. Scheller,et al.  The rat brain synucleins; family of proteins transiently associated with neuronal membrane. , 1991, Brain research. Molecular brain research.

[57]  R. Swerdlow,et al.  Abnormal Mitochondrial Morphology in Sporadic Parkinson's and Alzheimer's Disease Cybrid Cell Lines , 2000, Experimental Neurology.

[58]  Akihiko Iwai,et al.  The precursor protein of non-Aβ component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system , 1995, Neuron.

[59]  W. Tatton,et al.  Etiology and pathogenesis of Parkinson's disease. , 1999, Annual review of neuroscience.

[60]  Philippe Hantraye,et al.  MPTP induces alpha‐synuclein aggregation in the substantia nigra of baboons , 2000, Neuroreport.

[61]  J. Langston,et al.  The relationships between aging, monoamine oxidase, striatal dopamine and the effects of MPTP in C57BL/6 mice: a critical reassessment , 1992, Brain Research.

[62]  M. L. Schmidt,et al.  α-Synuclein in Lewy bodies , 1997, Nature.

[63]  P. Lansbury,et al.  Is there a cause-and-effect relationship between α-synuclein fibrillization and Parkinson’s disease? , 2000, Nature Cell Biology.

[64]  H. Niznik,et al.  Direct binding and functional coupling of α-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis. , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[65]  D. Neill,et al.  Aggregates from mutant and wild‐type α‐synuclein proteins and NAC peptide induce apoptotic cell death in human neuroblastoma cells by formation of β‐sheet and amyloid‐like filaments , 1998, FEBS letters.