Siah-1 Facilitates Ubiquitination and Degradation of Synphilin-1*

Parkinson's disease is a common neurodegenerative disorder characterized by loss of dopaminergic neurons and appearance of Lewy bodies, cytoplasmic inclusions that are highly enriched with ubiquitin. Synphilin-1, α-synuclein, and Parkin represent the major components of Lewy bodies and are involved in the pathogenesis of Parkinson's disease. Synphilin-1 is an α-synuclein-binding protein that is ubiquitinated by Parkin. Recently, a mutation in the synphilin-1 gene has been reported in patients with sporadic Parkinson's disease. Although synphilin-1 localizes close to synaptic vesicles, its function remains unknown. To investigate the proteins that interact with synphilin-1, the present study performed a yeast two-hybrid screening and identified a novel interacting protein, Siah-1 ubiquitin ligase. Synphilin-1 and Siah-1 proteins were endogenously expressed in the central nervous system and were found to coimmunoprecipitate each other in rat brain homogenate. Confocal microscopic analysis revealed colocalization of both proteins in cells. Siah-1 was found to interact with the N terminus of synphilin-1 through its substrate-binding domain and to specifically ubiquitinate synphilin-1 via its RING finger domain. Siah-1 facilitated synphilin-1 degradation via the ubiquitin-proteasome pathway more efficiently than Parkin. Siah-1 was found to not facilitate ubiquitination and degradation of wild type or mutant α-synuclein. Synphilin-1 inhibited high K+-induced dopamine release from PC12 cells. Siah-1 was found to abrogate the inhibitory effects of synphilin-1 on dopamine release. Such findings suggest that Siah-1 might play a role in regulation of synphilin-1 function.

[1]  D. Hernandez,et al.  Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease. , 2003, Human molecular genetics.

[2]  David D L Bowtell,et al.  A binding motif for Siah ubiquitin ligase , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[3]  A. Abeliovich,et al.  Parkin Is a Component of an SCF-like Ubiquitin Ligase Complex and Protects Postmitotic Neurons from Kainate Excitotoxicity , 2003, Neuron.

[4]  C. Ni,et al.  Structural Analysis of Siah1 and Its Interactions with Siah-interacting Protein (SIP)* , 2003, The Journal of Biological Chemistry.

[5]  J. Vavalle,et al.  Staring, a Novel E3 Ubiquitin-Protein Ligase That Targets Syntaxin 1 for Degradation* , 2002, The Journal of Biological Chemistry.

[6]  J. R. Menezes,et al.  Synphilin-1 Is Developmentally Localized to Synaptic Terminals, and Its Association with Synaptic Vesicles Is Modulated by α-Synuclein* , 2002, The Journal of Biological Chemistry.

[7]  Tetsuya Takahashi,et al.  Activation of Pyk2/RAFTK induces tyrosine phosphorylation of α‐synuclein via Src‐family kinases , 2002 .

[8]  Shigenobu Nakamura,et al.  Tyrosine 125 of α-synuclein plays a critical role for dimerization following nitrative stress , 2002, Brain Research.

[9]  F. L. Roudabush,et al.  Regulation of Synaptophysin Degradation by Mammalian Homologues of Seven in Absentia * , 2002, The Journal of Biological Chemistry.

[10]  E. Kondo,et al.  Lack of binding observed between human α-synuclein and Bcl-2 protein family , 2001, Neuroscience Letters.

[11]  A. Israël,et al.  Siah-1 binds and regulates the function of Numb , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[12]  P. Raychaudhuri,et al.  The Xeroderma Pigmentosum Group E Gene Product DDB2 Is a Specific Target of Cullin 4A in Mammalian Cells , 2001, Molecular and Cellular Biology.

[13]  S. Ikeda,et al.  A role for Seven in Absentia Homolog (Siah1a) in metabotropic glutamate receptor signaling , 2001, BMC Neuroscience.

[14]  C. Ross,et al.  Parkin ubiquitinates the α-synuclein–interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease , 2001, Nature Medicine.

[15]  L. Frati,et al.  Ubiquitination and degradation of Syk and ZAP-70 protein tyrosine kinases in human NK cells upon CD16 engagement , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[16]  J. Newell,et al.  The RING finger protein Siah‐1 regulates the level of the transcriptional coactivator OBF‐1 , 2001, The EMBO journal.

[17]  L. Staudt,et al.  Regulation of BOB.1/OBF.1 stability by SIAH , 2001, The EMBO journal.

[18]  N. Hattori,et al.  An Unfolded Putative Transmembrane Polypeptide, which Can Lead to Endoplasmic Reticulum Stress, Is a Substrate of Parkin , 2001, Cell.

[19]  B. Hyman,et al.  α-Synuclein–enhanced green fluorescent protein fusion proteins form proteasome sensitive inclusions in primary neurons , 2001, Neuroscience.

[20]  J C Reed,et al.  Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin degradation linked to p53 responses. , 2001, Molecular cell.

[21]  Raymond L. White,et al.  Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein. , 2001, Molecular cell.

[22]  Tetsuya Takahashi,et al.  Activated Fyn phosphorylates alpha-synuclein at tyrosine residue 125. , 2001, Biochemical and biophysical research communications.

[23]  N. Varin‐Blank,et al.  SIAH-1 interacts with α-tubulin and degrades the kinesin Kid by the proteasome pathway during mitosis , 2000, Oncogene.

[24]  Y. Imai,et al.  Parkin Suppresses Unfolded Protein Stress-induced Cell Death through Its E3 Ubiquitin-protein Ligase Activity* , 2000, The Journal of Biological Chemistry.

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

[26]  John Calvin Reed,et al.  p53 Suppresses the c-Myb-induced Activation of Heat Shock Transcription Factor 3* , 2000, The Journal of Biological Chemistry.

[27]  C A Ross,et al.  Synphilin‐1 is present in Lewy bodies in Parkinson's disease , 2000, Annals of neurology.

[28]  D. Bowtell,et al.  Pw1/Peg3 is a potential cell death mediator and cooperates with Siah1a in p53-mediated apoptosis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Heidi Phillips,et al.  Mice Lacking α-Synuclein Display Functional Deficits in the Nigrostriatal Dopamine System , 2000, Neuron.

[30]  S. Nakanishi,et al.  Competitive interaction of Seven in absentia homolog‐1A and Ca2+/calmodulin with the cytoplasmic tail of group 1 metabotropic glutamate receptors , 1999, Genes to cells : devoted to molecular & cellular mechanisms.

[31]  M. Kitagawa,et al.  An F‐box protein, FWD1, mediates ubiquitin‐dependent proteolysis of β‐catenin , 1999, The EMBO journal.

[32]  P. Worley,et al.  Synphilin-1 associates with α-synuclein and promotes the formation of cytosolic inclusions , 1999, Nature Genetics.

[33]  E. Fearon,et al.  Siah-1 N-Terminal RING Domain Is Required for Proteolysis Function, and C-Terminal Sequences Regulate Oligomerization and Binding to Target Proteins , 1999, Molecular and Cellular Biology.

[34]  M. L. Schmidt,et al.  Pathobiology of the Lewy body. , 1999, Advances in neurology.

[35]  M. Guenther,et al.  Proteasomal regulation of nuclear receptor corepressor-mediated repression. , 1998, Genes & development.

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

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

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

[39]  T. P. Neufeld,et al.  A genetic screen to identify components of the sina signaling pathway in Drosophila eye development. , 1998, Genetics.

[40]  A. Look,et al.  Characterization of human homologs of the Drosophila seven in absentia (sina) gene. , 1997, Genomics.

[41]  M. Vidal,et al.  Mammalian homologs of seven in absentia regulate DCC via the ubiquitin-proteasome pathway. , 1997, Genes & development.

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

[43]  T. P. Neufeld,et al.  PHYL Acts to Down-Regulate TTK88, a Transcriptional Repressor of Neuronal Cell Fates, by a SINA-Dependent Mechanism , 1997, Cell.

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

[45]  D. Bowtell,et al.  Chromosomal mapping of five highly conserved murine homologues of the Drosophila RING finger gene seven-in-absentia. , 1997, Genomics.

[46]  Tetsuya Takahashi,et al.  Inhibitory Effect of MK-801 on Amantadine-Induced Dopamine Release in the Rat Striatum , 1996, Brain Research Bulletin.

[47]  L. Forno,et al.  Neuropathology of Parkinson's Disease , 1996, Journal of neuropathology and experimental neurology.

[48]  D. Dickson,et al.  Pathology and Biology of the Lewy Body , 1993, Journal of neuropathology and experimental neurology.

[49]  E. Hafen,et al.  Raf functions downstream of Rasl in the Sevenless signal transduction pathway , 1992, Nature.

[50]  G. Rubin,et al.  Signalling by the sevenless protein tyrosine kinase is mimicked by Rasl activation , 1992, Nature.

[51]  G. Rubin,et al.  seven in absentia, a gene required for specification of R7 cell fate in the Drosophila eye , 1990, Cell.