Strain-specific morphology and CNS propagation of template-directed SOD1 aggregation following peripheral nerve inoculation

Abstract Accumulation of misfolded SOD1 protein into intracellular aggregates, in the spinal cord (SpC) and brainstem, is a hallmark of amyotrophic lateral sclerosis caused by mutations in the SOD1 gene (SOD1-ALS). Two distinct aggregate conformations, denoted strain A and strain B, were identified in the CNS of SOD1 G85R and SOD1 D90A transgenic (Tg) ALS mouse models, respectively. Both strains transmit templated SOD1 aggregation and ALS-like disease in Tg mouse models when inoculated into the SpC, whereas muscle or intraperitoneal inoculations, of up to 300 times more inoculate, did not. Here, we used strain A and strain B aggregate seeds, prepared from SpCs of the Tg mice, to investigate strain-specific differences in transmission of templated aggregation and ALS phenotype via a peripheral nerve. We show that both strains can transmit templated aggregation to the CNS via the sciatic nerve in SOD1 G85R Tg mice. Strain A resulted in shorter time to disease onset and earlier end-stage disease compared to strain B, and these strain-specific differences were accentuated in the sciatic nerve inoculation model compared to direct SpC inoculations. To further analyse the differences between strain A and strain B, we developed an immunohistochemical method that distinguishes the two SOD1 aggregate strains in tissue sections. This method revealed that strain B adopts an elongated, skein-like morphology, whereas strain A aggregates appear as accumulations of rounded, bead-like structures. These findings suggest that SOD1 aggregates forming in a peripheral nerve might transmit disease to the CNS and that different SOD1 aggregate strains can influence disease onset and progression. Our results warrant further exploratory studies of SOD1 aggregate conformations and their potential role in the manifestation of SOD1 mutant-specific disease phenotypes.