LAUSR

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 (αSOD1 143–153 ). Both pre-incubation of seeds with αSOD1 143–153 prior to inoculation, and weekly intraperitoneal (i.p.) administration attenuated transmission of pathogenic aggregation and prolonged the survival of seed-inoculated hSOD1 G85R Tg mice. In contrast, administration of a mAb targeting aa 65–72 (αSOD1 65–72 ), 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 αSOD1 143–153 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 αSOD1 143–153 was unable to prolong the lifespan of non-inoculated hSOD1 G85R Tg mice. Thus, spontaneously initiated hSOD1 aggregation in spinal motor neurons may be poorly accessible to therapeutic antibodies.