title: A natural human IgM that binds to gangliosides is therapeutic in murine models of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a devastating, fatal neurological disease that primarily affects spinal cord anterior horn cells and their axons for which there is no treatment. Here we report the use of a recombinant natural human IgM that binds to the surface of neurons and supports neurite extension, rHIgM12, as a therapeutic strategy in murine models of human ALS. A single 200 µg intraperitoneal dose of rHIgM12 increases survival in two independent genetic-based mutant SOD1 mouse strains (SOD1G86R and SOD1G93A) by 8 and 10 days, delays the onset of neurological deficits by 16 days, delays the onset of weight loss by 5 days, and preserves spinal cord axons and anterior horn neurons. Immuno-overlay of thin layer chromatography and surface plasmon resonance show that rHIgM12 binds with high affinity to the complex gangliosides GD1a and GT1b. Addition of rHIgM12 to neurons in culture increases α-tubulin tyrosination levels, suggesting an alteration of microtubule dynamics. We previously reported that a single peripheral dose of rHIgM12 preserved neurological function in a murine model of demyelination with axon loss. Because rHIgM12 improves three different models of neurological disease, we propose that the IgM might act late in the cascade of neuronal stress and/or death by a broad mechanism.
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Denic
authors.affiliation: Department of Electrical and Computer Engineering, University of Minnesota, Minneapolis, MN 55455, USA Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Luke R
authors.initials: LR
authors.lastname: Jordan
authors.affiliation: Department of Electrical and Computer Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Wittenberg
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Warrington
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Bharath
authors.initials: B
authors.lastname: Wootla
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Louisa M
authors.initials: LM
authors.lastname: Papke
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Zoecklein
authors.affiliation: Department of Electrical and Computer Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Daehan
authors.initials: D
authors.lastname: Yoo
authors.affiliation: Department of Electrical and Computer Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Jonah
authors.initials: J
authors.lastname: Shaver
authors.affiliation: Department of Electrical and Computer Engineering, University of Minnesota, Minneapolis, MN 55455, USA Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA sang@umn.edu rodriguez.moses@mayo.edu.
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Oh
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Larry R
authors.initials: LR
authors.lastname: Pease
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA sang@umn.edu rodriguez.moses@mayo.edu.
authors.forename: Moses
authors.initials: M
authors.lastname: Rodriguez
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D018450:Disease Progression; D004306:Dose-Response Relationship, Immunologic; D000939:Epitopes / Q000737:chemistry; D005732:Gangliosides / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007075:Immunoglobulin M / Q000627:therapeutic use*; D008051:Lipid Bilayers / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008870:Microtubules / Q000378:metabolism; D008958:Models, Molecular; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011994:Recombinant Proteins / Q000627:therapeutic use; D012995:Solubility; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism; D020349:Surface Plasmon Resonance; D016019:Survival Analysis; D014404:Tubulin / Q000378:metabolism
chemical_list: D000939:Epitopes; D005732:Gangliosides; D007075:Immunoglobulin M; D008051:Lipid Bilayers; D011994:Recombinant Proteins; D014404:Tubulin; C021298:ganglioside, GD1a; C016481:trisialoganglioside GT1; D013482:Superoxide Dismutase
keywords: ALS; Amyotrophic lateral sclerosis; Axon growth; GD1a; GT1b; Gangliosides; Neurite extension; Neuroprotection; SOD1; SPR; Supported lipid bilayers; Surface plasmon resonance