Intracisternal injection of two human SOD1 aggregate strains induces templated aggregation and ALS in transgenic...

Cytosolic aggregates containing misfolded superoxide dismutase-1 (SOD1) protein is an established hallmark of ALS caused by mutations in the SOD1 gene. We have previously identified two structurally distinct strains of human (h) SOD1 aggregates (denoted A and B) in mice transgenic (Tg) for hSOD1. Strain A and B have both been shown to transmit templated aggregation and induce early-onset of fatal ALS-like disease when injected directly into the spinal cord or peripheral nerve of hSOD1 Tg mice. In contrast, peripheral administration of hSOD1 aggregates into the intraperitoneal cavity or skeletal muscle did not induce disease. Collectively, these studies provide insight on the spreading mechanism of SOD1. However, the complete map of propagation routes and underlying mechanisms utilized by SOD1 aggregates in ALS is not fully charted. Here, we investigated whether hSOD1 aggregates may spread to the central nervous system (CNS) via the cerebrospinal fluid (CSF). Mutant hSOD1 aggregate seeds or control samples prepared from spinal cords of hSOD1 Tg mice or non-Tg mice, respectively, were inoculated into the cisterna magna of adult 100-day-old Tg mice expressing the G85R mutated hSOD1 protein. Disease phenotyping as well as biochemical and immunohistochemical analyses were performed and compared across the experimental groups. The mice inoculated with hSOD1 seeds developed early signs of ALS by 90 days after inoculation and reached terminal stage approximately 180 days earlier than mice receiving control seeds. Additionally, both strain A and B were observed to initiate templated aggregation along the neuroaxis. The results show that hSOD1 aggregates are capable of transmitting from the CSF to the CNS where they induce ALS-like pathology and concomitant phenotype. Unraveling the propagation pathways utilized by SOD1 opens new avenues to assess treatment strategies against ALS.