transport in Amyotrophic Lateral Sclerosis

Cu/Zn-superoxide dismutase (SOD1) is misfolded in familial and sporadic Amyotrophic Lateral Sclerosis (ALS), but it is not clear how this triggers endoplasmic reticulum (ER) stress or other pathogenic processes. Here we demonstrate that mutant SOD1 (mSOD1) is predominantly found in the cytoplasm in neuronal cells. Furthermore, we show that mSOD1 inhibits secretory protein transport from the ER to Golgi apparatus. ER-Golgi transport is linked to ER stress, Golgi fragmentation and axonal transport and we also show that inhibition of ER-Golgi trafficking preceded ER stress, Golgi fragmentation, protein aggregation and apoptosis in cells expressing mSOD1. Restoration of ER-Golgi transport by over-expression of coatomer coat protein II (COPII) subunit Sar1 protected against inclusion formation and apoptosis, thus linking dysfunction in ER-Golgi transport to cellular pathology. These findings thus link several cellular events in ALS into a single mechanism occurring early in mSOD1 expressing cells.

[1]  Timothy P. Levine,et al.  The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs , 2013, Bioinform..

[2]  J. Ihle,et al.  An Early Onset Progressive Motor Neuron Disorder in Scyl1-Deficient Mice Is Associated with Mislocalization of TDP-43 , 2012, The Journal of Neuroscience.

[3]  Bruce L. Miller,et al.  Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS , 2011, Neuron.

[4]  Andrés Couve,et al.  The endoplasmic reticulum and protein trafficking in dendrites and axons. , 2011, Trends in cell biology.

[5]  M. Tuszynski,et al.  Potential therapeutic uses of BDNF in neurological and psychiatric disorders , 2011, Nature Reviews Drug Discovery.

[6]  Emmanuel J. Botzolakis,et al.  The effect of HSP-causing mutations in SPG3A and NIPA1 on the assembly, trafficking, and interaction between atlastin-1 and NIPA1 , 2011, Molecular and Cellular Neuroscience.

[7]  Patrizia Sola,et al.  Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS , 2011, Neuron.

[8]  Erik Sahai,et al.  Deficits in axonal transport precede ALS symptoms in vivo , 2010, Proceedings of the National Academy of Sciences.

[9]  Katy E. Routledge,et al.  Emergent properties of proteostasis-COPII coupled systems in human health and disease , 2010, Molecular membrane biology.

[10]  Jeffery N Agar,et al.  Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS , 2010, Nature Neuroscience.

[11]  Johan Jacobsson,et al.  Novel Antibodies Reveal Inclusions Containing Non-Native SOD1 in Sporadic ALS Patients , 2010, PloS one.

[12]  Simon C Watkins,et al.  Sar1 assembly regulates membrane constriction and ER export , 2010, The Journal of cell biology.

[13]  J. Goldberg,et al.  Structure of Coatomer Cage Proteins and the Relationship among COPI, COPII, and Clathrin Vesicle Coats , 2010, Cell.

[14]  L. Greensmith,et al.  The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1G93A Mouse Model for Motor Neuron Disease* , 2010, The Journal of Biological Chemistry.

[15]  S. Sasaki.  Endoplasmic Reticulum Stress in Motor Neurons of the Spinal Cord in Sporadic Amyotrophic Lateral Sclerosis , 2010, Journal of neuropathology and experimental neurology.

[16]  Paul G. Ince,et al.  Mutations in CHMP2B in Lower Motor Neuron Predominant Amyotrophic Lateral Sclerosis (ALS) , 2010, PloS one.

[17]  Yi Zhang,et al.  Cell Surface Relocalization of the Endoplasmic Reticulum Chaperone and Unfolded Protein Response Regulator GRP78/BiP* , 2010, The Journal of Biological Chemistry.

[18]  N. Harel,et al.  Reticulon-4A (Nogo-A) Redistributes Protein Disulfide Isomerase to Protect Mice from SOD1-Dependent Amyotrophic Lateral Sclerosis , 2009, The Journal of Neuroscience.

[19]  K. Fish,et al.  Selective Targeting of ER Exit Sites Supports Axon Development , 2009, Traffic.

[20]  D. R. Laybutt,et al.  Reduced endoplasmic reticulum (ER)-to-Golgi protein trafficking contributes to ER stress in lipotoxic mouse beta cells by promoting protein overload , 2009, Diabetologia.

[21]  D. Stephens,et al.  Specificity of cytoplasmic dynein subunits in discrete membrane-trafficking steps. , 2009, Molecular biology of the cell.

[22]  P. Caroni,et al.  A role for motoneuron subtype–selective ER stress in disease manifestations of FALS mice , 2009, Nature Neuroscience.

[23]  M. Horne,et al.  Recruitment of mitochondria into apoptotic signaling correlates with the presence of inclusions formed by amyotrophic lateral sclerosis‐associated SOD1 mutations , 2009, Journal of neurochemistry.

[24]  H. Sitte,et al.  Sec24- and ARFGAP1-Dependent Trafficking of GABA Transporter-1 Is a Prerequisite for Correct Axonal Targeting , 2008, The Journal of Neuroscience.

[25]  J. Ngsee,et al.  FFAT rescues VAPA-mediated inhibition of ER-to-Golgi transport and VAPB-mediated ER aggregation , 2008, Journal of Cell Science.

[26]  S. Lev,et al.  Coordinated lipid transfer between the endoplasmic reticulum and the Golgi complex requires the VAP proteins and is essential for Golgi-mediated transport. , 2008, Molecular biology of the cell.

[27]  T. Adachi.  [Case of multiple brain infarction with MPO-ANCA]. , 2008, Brain and nerve = Shinkei kenkyu no shinpo.

[28]  Randy Schekman,et al.  Coordination of COPII vesicle trafficking by Sec23. , 2008, Trends in cell biology.

[29]  I. Tooyama,et al.  The endoplasmic reticulum‐Golgi pathway is a target for translocation and aggregation of mutant superoxide dismutase linked to ALS , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[30]  Takanori Yokota,et al.  Als-linked Mutant Sod1 Induces Er Stress-and Ask1-dependent Motor Neuron Death by Targeting Derlin-1 -induced Cell Death Remains Controversial. Here We Show That Sod1 Mut Specifically Interacted with Derlin-1, a Component of Endoplasmic Reticulum (er)-associated Degradation (erad) Machinery and Trig , 2022 .

[31]  D. Price,et al.  Motor Neuron Disease Occurring in a Mutant Dynactin Mouse Model Is Characterized by Defects in Vesicular Trafficking , 2008, The Journal of Neuroscience.

[32]  Stuart A. Lipton,et al.  A Golgi fragmentation pathway in neurodegeneration , 2008, Neurobiology of Disease.

[33]  H. Cai,et al.  The G59S Mutation in p150glued Causes Dysfunction of Dynactin in Mice , 2007, The Journal of Neuroscience.

[34]  Y. Jan,et al.  Growing Dendrites and Axons Differ in Their Reliance on the Secretory Pathway , 2007, Cell.

[35]  C. Lopez,et al.  Progressive Motor Neuronopathy: A Critical Role of the Tubulin Chaperone TBCE in Axonal Tubulin Routing from the Golgi Apparatus , 2007, The Journal of Neuroscience.

[36]  M. Jäättelä,et al.  Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium , 2007, Cell Death and Differentiation.

[37]  L. Hayward,et al.  Interaction between Familial Amyotrophic Lateral Sclerosis (ALS)-linked SOD1 Mutants and the Dynein Complex* , 2007, Journal of Biological Chemistry.

[38]  D. Ito,et al.  Molecular pathogenesis of seipin/BSCL2‐related motor neuron diseases , 2007, Annals of neurology.

[39]  L. Neckers,et al.  Endoplasmic Reticulum Vacuolization and Valosin-Containing Protein Relocalization Result from Simultaneous Hsp90 Inhibition by Geldanamycin and Proteasome Inhibition by Velcade , 2006, Molecular Cancer Research.

[40]  Bryan F. Shaw,et al.  Local Unfolding in a Destabilized, Pathogenic Variant of Superoxide Dismutase 1 Observed with H/D Exchange and Mass Spectrometry* , 2006, Journal of Biological Chemistry.

[41]  G. McKhann,et al.  Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS model. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[42]  A. Lengeling,et al.  Mutation of Vps54 causes motor neuron disease and defective spermiogenesis in the wobbler mouse , 2005, Nature Genetics.

[43]  G. Spudich,et al.  Optineurin links myosin VI to the Golgi complex and is involved in Golgi organization and exocytosis , 2005, The Journal of cell biology.

[44]  A. Hill,et al.  Impaired Extracellular Secretion of Mutant Superoxide Dismutase 1 Associates with Neurotoxicity in Familial Amyotrophic Lateral Sclerosis , 2005, The Journal of Neuroscience.

[45]  T. Gillingwater,et al.  A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. , 2004, American journal of human genetics.

[46]  E. O’Shea,et al.  Global analysis of protein expression in yeast , 2003, Nature.

[47]  Shin J. Oh,et al.  Mutant dynactin in motor neuron disease , 2003, Nature Genetics.

[48]  D. Greco,et al.  The Cu,Zn superoxide dismutase in neuroblastoma SK-N-BE cells is exported by a microvesicles dependent pathway. , 2003, Brain research. Molecular brain research.

[49]  C. Turano,et al.  Proteins of the PDI family: Unpredicted non‐ER locations and functions , 2002, Journal of cellular physiology.

[50]  B. Glick,et al.  Dynamics of transitional endoplasmic reticulum sites in vertebrate cells. , 2000, Molecular biology of the cell.

[51]  P. Gleeson,et al.  Medial Golgi but Not Late Golgi Glycosyltransferases Exist as High Molecular Weight Complexes , 2000, The Journal of Biological Chemistry.

[52]  J. Lippincott-Schwartz,et al.  Kinetic Analysis of Secretory Protein Traffic and Characterization of Golgi to Plasma Membrane Transport Intermediates in Living Cells , 1998, The Journal of cell biology.

[53]  M. Santillo,et al.  Evidence for secretion of cytosolic CuZn superoxide dismutase by Hep G2 cells and human fibroblasts. , 1996, The international journal of biochemistry & cell biology.

[54]  M. Gurney,et al.  The Golgi apparatus of spinal cord motor neurons in transgenic mice expressing mutant Cu,Zn superoxide dismutase becomes fragmented in early, preclinical stages of the disease. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[55]  J. Haines,et al.  Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis , 1993, Nature.

[56]  Z. Mourelatos,et al.  Fragmentation of the Golgi apparatus of motor neurons in amyotrophic lateral sclerosis revealed by organelle-specific antibodies. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[57]  J. Crapo,et al.  Molecular immunocytochemistry of the CuZn superoxide dismutase in rat hepatocytes , 1988, The Journal of cell biology.

[58]  Mark Ellisman,et al.  Evidence that all newly synthesized proteins destined for fast axonal transport pass through the Golgi apparatus , 1982, The Journal of cell biology.

[59]  M. Horne,et al.  Protein disulphide isomerase protects against protein aggregation and is S-nitrosylated in amyotrophic lateral sclerosis. , 2010, Brain : a journal of neurology.

[60]  J. Lippincott-Schwartz,et al.  The fluorescence protease protection (FPP) assay to determine protein localization and membrane topology , 2006, Nature Protocols.

[61]  A. Sik,et al.  Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis , 2006, Nature Neuroscience.

[62]  Rainer Pepperkok,et al.  Coupling of ER exit to microtubules through direct interaction of COPII with dynactin , 2005, Nature Cell Biology.