Aggregate-selective antibody attenuates seeded aggregation but not spontaneously evolving disease in SOD1 ALS model mice
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RESEARCH
Aggregate‑selective antibody attenuates seeded aggregation but not spontaneously evolving disease in SOD1 ALS model mice Manuela Lehmann1, Matthew Marklund2, Anna‑Lena Bolender1, Elaheh E. Bidhendi1, Per Zetterström3, Peter M. Andersen1, Thomas Brännström2, Stefan L. Marklund3, Jonathan D. Gilthorpe4 and Ulrika Nordström1*
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 aggrega‑ tion 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 acces‑ sible to therapeutic antibodies. Keywords: ALS, SOD1, Template directed aggregation, Prion-like, Immunotherapy, Neurodegenerative disease Introduction ALS is characterized by a progressing adult-onset neuromuscular degeneration. The first symptoms typically present as locally restricted paresis that spreads contiguously and eventually results in generalized paralysis *Correspondence: [email protected] 1 Department of Clinical Science, Neurosciences, Umeå University, 901 87 Umeå, Sweden Full list of author information is available at the end of the article
of most skeletal myotomes [11]. Death usually occurs within 1–3 years after first onset of paresis, as spreading paralysis engages the respiratory muscles [13]. Coding mutations in the superoxide dismutase 1 (SOD1) gene have been found in 2–6% of ALS patients with some variability among populations [1]. Most ALSlinked SOD1 mutations destab
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