Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis.
Elaheh Ekhtiari BidhendiJohan BerghPer ZetterströmKarin ForsbergBente PakkenbergPeter M AndersenStefan L MarklundThomas BrännströmPublished in: Acta neuropathologica (2018)
Motor neurons containing aggregates of superoxide dismutase 1 (SOD1) are hallmarks of amyotrophic lateral sclerosis (ALS) caused by mutations in the gene encoding SOD1. We have previously reported that two strains of mutant human (h) SOD1 aggregates (denoted A and B) can arise in hSOD1-transgenic models for ALS and that inoculation of such aggregates into the lumbar spinal cord of mice results in rostrally spreading, templated hSOD1 aggregation and premature fatal ALS-like disease. Here, we explored whether mutant hSOD1 aggregates with prion-like properties also exist in human ALS. Aggregate seeds were prepared from spinal cords from an ALS patient carrying the hSOD1G127Gfs*7 truncation mutation and from mice transgenic for the same mutation. To separate from mono-, di- or any oligomeric hSOD1 species, the seed preparation protocol included ultracentrifugation through a density cushion. The core structure of hSOD1G127Gfs*7 aggregates present in mice was strain A-like. Inoculation of the patient- or mouse-derived seeds into lumbar spinal cord of adult hSOD1-expressing mice induced strain A aggregation propagating along the neuraxis and premature fatal ALS-like disease (p < 0.0001). Inoculation of human or murine control seeds had no effect. The potencies of the ALS patient-derived seed preparations were high and disease was initiated in the transgenic mice by levels of hSOD1G127Gfs*7 aggregates much lower than those found in the motor system of patients carrying the mutation. The results suggest that prion-like growth and spread of hSOD1 aggregation could be the primary pathogenic mechanism, not only in hSOD1 transgenic rodent models, but also in human ALS.
Keyphrases
- amyotrophic lateral sclerosis
- spinal cord
- endothelial cells
- induced pluripotent stem cells
- spinal cord injury
- high glucose
- high fat diet induced
- type diabetes
- wild type
- oxidative stress
- gene expression
- case report
- minimally invasive
- ejection fraction
- randomized controlled trial
- dna methylation
- staphylococcus aureus
- diabetic rats
- hydrogen peroxide
- transcription factor
- genome wide
- tandem mass spectrometry
- copy number