Proteasome Mediates Dopaminergic Neuronal Degeneration, and Its Inhibition Causes α-Synuclein Inclusions*

Parkinson's disease is characterized by dopaminergic neuronal death and the presence of Lewy bodies. α-Synuclein is a major component of Lewy bodies, but the process of its accumulation and its relationship to dopaminergic neuronal death has not been resolved. Although the pathogenesis has not been clarified, mitochondrial complex I is suppressed, and caspase-3 is activated in the affected midbrain. Here we report that a combination of 1-methyl-4-phenylpyridinium ion (MPP+) or rotenone and proteasome inhibition causes the appearance of α-synuclein-positive inclusion bodies. Unexpectedly, however, proteasome inhibition blocked MPP+- or rotenone-induced dopaminergic neuronal death. MPP+ elevated proteasome activity, dephosphorylated mitogen-activating protein kinase (MAPK), and activated caspase-3. Proteasome inhibition reversed the MAPK dephosphorylation and blocked caspase-3 activation; the neuroprotection was blocked by a p42 and p44 MAPK kinase inhibitor. Thus, the proteasome plays an important role in both inclusion body formation and dopaminergic neuronal death but these processes form opposite sides on the proteasome regulation in this model.

[1]  T. Hunter,et al.  The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2. , 2002, Molecular cell.

[2]  T. Ozawa,et al.  Immunohistochemical studies on complexes I, II, III, and IV of mitochondria in parkinson's disease , 1991, Annals of neurology.

[3]  M. Vila,et al.  MPTP: a review of its mechanisms of neurotoxicity , 2001, Clinical Neuroscience Research.

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

[5]  N. Quinn,et al.  Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations , 2001, Neurology.

[6]  J. Ting,et al.  MEK Inhibition Enhances Paclitaxel-induced Tumor Apoptosis* , 2000, The Journal of Biological Chemistry.

[7]  D. Sulzer,et al.  Proteasomal inhibition leads to formation of ubiquitin/α‐synuclein‐immunoreactive inclusions in PC12 cells , 2001, Journal of neurochemistry.

[8]  C. Olanow,et al.  Impairment of the ubiquitin‐proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures , 2002, Journal of neurochemistry.

[9]  A. Asai,et al.  Proteasome Inhibitors Induce Cytochrome c–Caspase-3-Like Protease-Mediated Apoptosis in Cultured Cortical Neurons , 2000, The Journal of Neuroscience.

[10]  R. Crowther,et al.  α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies , 1998 .

[11]  W. Risau,et al.  Inhibition of proteasome function induces programmed cell death in proliferating endothelial cells , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[12]  V. L. Johnson,et al.  MAPK/ERK signaling in activated T cells inhibits CD95/Fas‐mediated apoptosis downstream of DISC assembly , 2000, The EMBO journal.

[13]  T. Dawson,et al.  Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Todd B. Sherer,et al.  Subcutaneous Rotenone Exposure Causes Highly Selective Dopaminergic Degeneration and α-Synuclein Aggregation , 2003, Experimental Neurology.

[15]  A. Goldberg,et al.  Cellular Defenses against Unfolded Proteins A Cell Biologist Thinks about Neurodegenerative Diseases , 2001, Neuron.

[16]  D. Jacobowitz,et al.  A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[17]  T. Oury,et al.  Cytoplasmic aggregates of phosphorylated extracellular signal-regulated protein kinases in Lewy body diseases. , 2002, The American journal of pathology.

[18]  C. Barbato,et al.  Proteasome Involvement and Accumulation of Ubiquitinated Proteins in Cerebellar Granule Neurons Undergoing Apoptosis , 2000, The Journal of Neuroscience.

[19]  I. Ferrer,et al.  Active, phosphorylation-dependent mitogen-activated protein kinase (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 kinase expression in Parkinson's disease and Dementia with Lewy bodies , 2001, Journal of Neural Transmission.

[20]  A. Tolkovsky,et al.  The Ras/Phosphatidylinositol 3-Kinase and Ras/ERK Pathways Function as Independent Survival Modules Each of Which Inhibits a Distinct Apoptotic Signaling Pathway in Sympathetic Neurons* , 2000, The Journal of Biological Chemistry.

[21]  K. McNaught,et al.  Proteasomal function is impaired in substantia nigra in Parkinson's disease , 2001, Neuroscience Letters.

[22]  E. Hirsch,et al.  Caspase-3: A vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson's disease. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Bertrand Friguet,et al.  Dysfunction of mitochondrial complex I and the proteasome: interactions between two biochemical deficits in a cellular model of Parkinson's disease , 2003, Journal of neurochemistry.

[24]  T. Chase,et al.  Degradation of α-Synuclein by Proteasome* , 1999, The Journal of Biological Chemistry.

[25]  D. Hernandez,et al.  Lewy bodies and parkinsonism in families with parkin mutations , 2001, Annals of neurology.

[26]  S Shimohama,et al.  Different mechanisms of glutamate‐induced neuronal death between dopaminergic and non‐dopaminergic neurons in rat mesencephalic culture , 1996, Journal of neuroscience research.

[27]  N. Tatton.  Increased Caspase 3 and Bax Immunoreactivity Accompany Nuclear GAPDH Translocation and Neuronal Apoptosis in Parkinson's Disease , 2000, Experimental Neurology.

[28]  P. Lockhart,et al.  Parkin Protects against the Toxicity Associated with Mutant α-Synuclein Proteasome Dysfunction Selectively Affects Catecholaminergic Neurons , 2002, Neuron.

[29]  J. Martinou,et al.  Involvement of the proteasome in the programmed cell death of NGF‐deprived sympathetic neurons. , 1996, The EMBO journal.

[30]  R. Ramsay,et al.  Uptake of the neurotoxin 1-methyl-4-phenylpyridine (MPP+) by mitochondria and its relation to the inhibition of the mitochondrial oxidation of NAD+-linked substrates by MPP+. , 1986, Biochemical and biophysical research communications.

[31]  W. Honer,et al.  Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders. , 1998, The American journal of pathology.

[32]  M. Naoi,et al.  N-methyl-(R)salsolinol as a dopaminergic neurotoxin: from an animal model to an early marker of Parkinson's disease. , 1997, Journal of neural transmission. Supplementum.

[33]  T. Kondo,et al.  Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q , 1998, Neurology.

[34]  N. Sone,et al.  Effects of 1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine and 1‐Methyl‐4‐Phenylpyridinium Ion on Activities of the Enzymes in the Electron Transport System in Mouse Brain , 1987, Journal of neurochemistry.

[35]  S. E. F. Tran,et al.  MAPK/ERK Overrides the Apoptotic Signaling from Fas, TNF, and TRAIL Receptors* , 2001, The Journal of Biological Chemistry.

[36]  C. Olanow,et al.  Proteasome inhibition causes nigral degeneration with inclusion bodies in rats , 2002, Neuroreport.

[37]  I. Ferrer,et al.  Bcl-2 and Bax proteins in lewy bodies from patients with Parkinson's disease and Diffuse Lewy body disease , 1997, Neuroscience Letters.

[38]  J. Darbon,et al.  Cell adhesion protects c-Raf-1 against ubiquitin-dependent degradation by the proteasome. , 2002, Biochemical and Biophysical Research Communications - BBRC.

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

[40]  S. Tabrizi,et al.  Mitochondria in the etiology and pathogenesis of parkinson's disease , 1998, Annals of neurology.

[41]  Shinsei Minoshima,et al.  Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase , 2000, Nature Genetics.

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

[43]  A. Eastman,et al.  Inhibition of extracellular signal-regulated kinase (ERK) mediates cell cycle phase independent apoptosis in vinblastine-treated ML-1 cells. , 2001, Cancer research.

[44]  L. Neckers,et al.  Geldanamycin-induced destabilization of Raf-1 involves the proteasome. , 1997, Biochemical and biophysical research communications.

[45]  A. Goldberg,et al.  Proteasomes play an essential role in thymocyte apoptosis. , 1996, The EMBO journal.

[46]  Mark Guttman,et al.  Brain proteasomal function in sporadic Parkinson's disease and related disorders , 2002, Annals of neurology.

[47]  Keiko Hashimoto,et al.  Delayed and Sustained Activation of p42/p44 Mitogen‐Activated Protein Kinase Induced by Proteasome Inhibitors Through p21ras in PC12 Cells , 2000, Journal of neurochemistry.

[48]  S. Shimohama,et al.  Mechanisms of antiapoptotic effects of estrogens in nigral dopaminergic neurons , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[49]  J. Langston,et al.  Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. , 1983, Science.

[50]  Zhijian J. Chen,et al.  TAK1 is a ubiquitin-dependent kinase of MKK and IKK , 2001, Nature.

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

[52]  John Calvin Reed,et al.  MEK/ERK signaling pathway regulates the expression of Bcl‐2, Bcl‐XL, and Mcl‐1 and promotes survival of human pancreatic cancer cells , 2000, Journal of cellular biochemistry.