Aggregate-selective antibody attenuates seeded aggregation but not spontaneously evolving disease in SOD1 ALS model mice
Abstract Increasing evidence suggests that propagation of the motor neuron disease amyotrophic lateral sclerosis (ALS) involves the pathogenic aggregation of disease-associated proteins that spread in a prion-like manner. We have identified two aggregate strains of human superoxide dismutase 1 (hSOD...
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| Format: | Article |
| Language: | English |
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BMC
2020-09-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-020-01032-2 |
| _version_ | 1818385932107120640 |
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| author | Manuela Lehmann Matthew Marklund Anna-Lena Bolender Elaheh E. Bidhendi Per Zetterström Peter M. Andersen Thomas Brännström Stefan L. Marklund Jonathan D. Gilthorpe Ulrika Nordström |
| author_facet | Manuela Lehmann Matthew Marklund Anna-Lena Bolender Elaheh E. Bidhendi Per Zetterström Peter M. Andersen Thomas Brännström Stefan L. Marklund Jonathan D. Gilthorpe Ulrika Nordström |
| author_sort | Manuela Lehmann |
| collection | DOAJ |
| description | Abstract Increasing evidence suggests that propagation of the motor neuron disease amyotrophic lateral sclerosis (ALS) involves the pathogenic aggregation of disease-associated proteins that spread in a prion-like manner. We have identified two aggregate strains of human superoxide dismutase 1 (hSOD1) that arise in the CNS of transgenic mouse models of SOD1-mediated ALS. Both strains transmit template-directed aggregation and premature fatal paralysis when inoculated into the spinal cord of adult hSOD1 transgenic mice. This spread of pathogenic aggregation could be a potential target for immunotherapeutic intervention. Here we generated mouse monoclonal antibodies (mAbs) directed to exposed epitopes in hSOD1 aggregate strains and identified an aggregate selective mAb that targets the aa 143–153 C-terminal extremity of hSOD1 (αSOD1143–153). Both pre-incubation of seeds with αSOD1143–153 prior to inoculation, and weekly intraperitoneal (i.p.) administration attenuated transmission of pathogenic aggregation and prolonged the survival of seed-inoculated hSOD1G85R Tg mice. In contrast, administration of a mAb targeting aa 65–72 (αSOD165–72), which exhibits high affinity towards monomeric disordered hSOD1, had an adverse effect and aggravated seed induced premature ALS-like disease. Although the mAbs reached similar concentrations in CSF, only αSOD1143–153 was found in association with aggregated hSOD1 in spinal cord homogenates. Our results suggest that an aggregate-selective immunotherapeutic approach may suppress seeded transmission of pathogenic aggregation in ALS. However, long-term administration of αSOD1143–153 was unable to prolong the lifespan of non-inoculated hSOD1G85R Tg mice. Thus, spontaneously initiated hSOD1 aggregation in spinal motor neurons may be poorly accessible to therapeutic antibodies. |
| first_indexed | 2024-12-14T03:46:00Z |
| format | Article |
| id | doaj.art-36abdf0346ab411681ed231180153dc2 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-14T03:46:00Z |
| publishDate | 2020-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-36abdf0346ab411681ed231180153dc22022-12-21T23:18:21ZengBMCActa Neuropathologica Communications2051-59602020-09-018111810.1186/s40478-020-01032-2Aggregate-selective antibody attenuates seeded aggregation but not spontaneously evolving disease in SOD1 ALS model miceManuela Lehmann0Matthew Marklund1Anna-Lena Bolender2Elaheh E. Bidhendi3Per Zetterström4Peter M. Andersen5Thomas Brännström6Stefan L. Marklund7Jonathan D. Gilthorpe8Ulrika Nordström9Department of Clinical Science, Neurosciences, Umeå UniversityDepartment of Medical Biosciences, Pathology, Umeå UniversityDepartment of Clinical Science, Neurosciences, Umeå UniversityDepartment of Clinical Science, Neurosciences, Umeå UniversityDepartment of Medical Biosciences, Clinical Chemistry, Umeå UniversityDepartment of Clinical Science, Neurosciences, Umeå UniversityDepartment of Medical Biosciences, Pathology, Umeå UniversityDepartment of Medical Biosciences, Clinical Chemistry, Umeå UniversityDepartment of Integrative Medical Biology, Umeå UniversityDepartment of Clinical Science, Neurosciences, Umeå UniversityAbstract Increasing evidence suggests that propagation of the motor neuron disease amyotrophic lateral sclerosis (ALS) involves the pathogenic aggregation of disease-associated proteins that spread in a prion-like manner. We have identified two aggregate strains of human superoxide dismutase 1 (hSOD1) that arise in the CNS of transgenic mouse models of SOD1-mediated ALS. Both strains transmit template-directed aggregation and premature fatal paralysis when inoculated into the spinal cord of adult hSOD1 transgenic mice. This spread of pathogenic aggregation could be a potential target for immunotherapeutic intervention. Here we generated mouse monoclonal antibodies (mAbs) directed to exposed epitopes in hSOD1 aggregate strains and identified an aggregate selective mAb that targets the aa 143–153 C-terminal extremity of hSOD1 (αSOD1143–153). Both pre-incubation of seeds with αSOD1143–153 prior to inoculation, and weekly intraperitoneal (i.p.) administration attenuated transmission of pathogenic aggregation and prolonged the survival of seed-inoculated hSOD1G85R Tg mice. In contrast, administration of a mAb targeting aa 65–72 (αSOD165–72), which exhibits high affinity towards monomeric disordered hSOD1, had an adverse effect and aggravated seed induced premature ALS-like disease. Although the mAbs reached similar concentrations in CSF, only αSOD1143–153 was found in association with aggregated hSOD1 in spinal cord homogenates. Our results suggest that an aggregate-selective immunotherapeutic approach may suppress seeded transmission of pathogenic aggregation in ALS. However, long-term administration of αSOD1143–153 was unable to prolong the lifespan of non-inoculated hSOD1G85R Tg mice. Thus, spontaneously initiated hSOD1 aggregation in spinal motor neurons may be poorly accessible to therapeutic antibodies.http://link.springer.com/article/10.1186/s40478-020-01032-2ALSSOD1Template directed aggregationPrion-likeImmunotherapyNeurodegenerative disease |
| spellingShingle | Manuela Lehmann Matthew Marklund Anna-Lena Bolender Elaheh E. Bidhendi Per Zetterström Peter M. Andersen Thomas Brännström Stefan L. Marklund Jonathan D. Gilthorpe Ulrika Nordström Aggregate-selective antibody attenuates seeded aggregation but not spontaneously evolving disease in SOD1 ALS model mice Acta Neuropathologica Communications ALS SOD1 Template directed aggregation Prion-like Immunotherapy Neurodegenerative disease |
| title | Aggregate-selective antibody attenuates seeded aggregation but not spontaneously evolving disease in SOD1 ALS model mice |
| title_full | Aggregate-selective antibody attenuates seeded aggregation but not spontaneously evolving disease in SOD1 ALS model mice |
| title_fullStr | Aggregate-selective antibody attenuates seeded aggregation but not spontaneously evolving disease in SOD1 ALS model mice |
| title_full_unstemmed | Aggregate-selective antibody attenuates seeded aggregation but not spontaneously evolving disease in SOD1 ALS model mice |
| title_short | Aggregate-selective antibody attenuates seeded aggregation but not spontaneously evolving disease in SOD1 ALS model mice |
| title_sort | aggregate selective antibody attenuates seeded aggregation but not spontaneously evolving disease in sod1 als model mice |
| topic | ALS SOD1 Template directed aggregation Prion-like Immunotherapy Neurodegenerative disease |
| url | http://link.springer.com/article/10.1186/s40478-020-01032-2 |
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