The neuropathic potential of anti-GM1 autoantibodies is regulated by the local glycolipid environment in mice.
Anti-GM1 ganglioside autoantibodies are used as diagnostic markers for motor axonal peripheral neuropathies and are believed to be the primary mediators of such diseases. However, their ability to bind and exert pathogenic effects at neuronal membranes is highly inconsistent. Using human and mouse m...
| Hlavní autoři: | , , , , , , , , , , , , , |
|---|---|
| Médium: | Journal article |
| Jazyk: | English |
| Vydáno: |
2009
|
| _version_ | 1826259954252644352 |
|---|---|
| author | Greenshields, K Halstead, S Zitman, F Rinaldi, S Brennan, K O'Leary, C Chamberlain, L Easton, A Roxburgh, J Pediani, J Furukawa, K Furukawa, K Goodyear, C Plomp, J Willison, H |
| author_facet | Greenshields, K Halstead, S Zitman, F Rinaldi, S Brennan, K O'Leary, C Chamberlain, L Easton, A Roxburgh, J Pediani, J Furukawa, K Furukawa, K Goodyear, C Plomp, J Willison, H |
| author_sort | Greenshields, K |
| collection | OXFORD |
| description | Anti-GM1 ganglioside autoantibodies are used as diagnostic markers for motor axonal peripheral neuropathies and are believed to be the primary mediators of such diseases. However, their ability to bind and exert pathogenic effects at neuronal membranes is highly inconsistent. Using human and mouse monoclonal anti-GM1 antibodies to probe the GM1-rich motor nerve terminal membrane in mice, we here show that the antigenic oligosaccharide of GM1 in the live plasma membrane is cryptic, hidden on surface domains that become buried for a proportion of anti-GM1 antibodies due to a masking effect of neighboring gangliosides. The cryptic GM1 binding domain was exposed by sialidase treatment that liberated sialic acid from masking gangliosides including GD1a or by disruption of the live membrane by freezing or fixation. This cryptic behavior was also recapitulated in solid-phase immunoassays. These data show that certain anti-GM1 antibodies exert potent complement activation-mediated neuropathogenic effects, including morphological damage at living terminal motor axons, leading to a block of synaptic transmission. This occurred only when GM1 was topologically available for antibody binding, but not when GM1 was cryptic. This revised understanding of the complexities in ganglioside membrane topology provides a mechanistic account for wide variations in the neuropathic potential of anti-GM1 antibodies. |
| first_indexed | 2024-03-06T18:57:59Z |
| format | Journal article |
| id | oxford-uuid:128467bd-f4f3-46f6-9b55-b15c3735a35c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:57:59Z |
| publishDate | 2009 |
| record_format | dspace |
| spelling | oxford-uuid:128467bd-f4f3-46f6-9b55-b15c3735a35c2022-03-26T10:08:28ZThe neuropathic potential of anti-GM1 autoantibodies is regulated by the local glycolipid environment in mice.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:128467bd-f4f3-46f6-9b55-b15c3735a35cEnglishSymplectic Elements at Oxford2009Greenshields, KHalstead, SZitman, FRinaldi, SBrennan, KO'Leary, CChamberlain, LEaston, ARoxburgh, JPediani, JFurukawa, KFurukawa, KGoodyear, CPlomp, JWillison, HAnti-GM1 ganglioside autoantibodies are used as diagnostic markers for motor axonal peripheral neuropathies and are believed to be the primary mediators of such diseases. However, their ability to bind and exert pathogenic effects at neuronal membranes is highly inconsistent. Using human and mouse monoclonal anti-GM1 antibodies to probe the GM1-rich motor nerve terminal membrane in mice, we here show that the antigenic oligosaccharide of GM1 in the live plasma membrane is cryptic, hidden on surface domains that become buried for a proportion of anti-GM1 antibodies due to a masking effect of neighboring gangliosides. The cryptic GM1 binding domain was exposed by sialidase treatment that liberated sialic acid from masking gangliosides including GD1a or by disruption of the live membrane by freezing or fixation. This cryptic behavior was also recapitulated in solid-phase immunoassays. These data show that certain anti-GM1 antibodies exert potent complement activation-mediated neuropathogenic effects, including morphological damage at living terminal motor axons, leading to a block of synaptic transmission. This occurred only when GM1 was topologically available for antibody binding, but not when GM1 was cryptic. This revised understanding of the complexities in ganglioside membrane topology provides a mechanistic account for wide variations in the neuropathic potential of anti-GM1 antibodies. |
| spellingShingle | Greenshields, K Halstead, S Zitman, F Rinaldi, S Brennan, K O'Leary, C Chamberlain, L Easton, A Roxburgh, J Pediani, J Furukawa, K Furukawa, K Goodyear, C Plomp, J Willison, H The neuropathic potential of anti-GM1 autoantibodies is regulated by the local glycolipid environment in mice. |
| title | The neuropathic potential of anti-GM1 autoantibodies is regulated by the local glycolipid environment in mice. |
| title_full | The neuropathic potential of anti-GM1 autoantibodies is regulated by the local glycolipid environment in mice. |
| title_fullStr | The neuropathic potential of anti-GM1 autoantibodies is regulated by the local glycolipid environment in mice. |
| title_full_unstemmed | The neuropathic potential of anti-GM1 autoantibodies is regulated by the local glycolipid environment in mice. |
| title_short | The neuropathic potential of anti-GM1 autoantibodies is regulated by the local glycolipid environment in mice. |
| title_sort | neuropathic potential of anti gm1 autoantibodies is regulated by the local glycolipid environment in mice |
| work_keys_str_mv | AT greenshieldsk theneuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT halsteads theneuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT zitmanf theneuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT rinaldis theneuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT brennank theneuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT olearyc theneuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT chamberlainl theneuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT eastona theneuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT roxburghj theneuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT pedianij theneuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT furukawak theneuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT furukawak theneuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT goodyearc theneuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT plompj theneuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT willisonh theneuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT greenshieldsk neuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT halsteads neuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT zitmanf neuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT rinaldis neuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT brennank neuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT olearyc neuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT chamberlainl neuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT eastona neuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT roxburghj neuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT pedianij neuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT furukawak neuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT furukawak neuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT goodyearc neuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT plompj neuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice AT willisonh neuropathicpotentialofantigm1autoantibodiesisregulatedbythelocalglycolipidenvironmentinmice |