期刊
ACTA NEUROPATHOLOGICA
卷 136, 期 6, 页码 939-953出版社
SPRINGER
DOI: 10.1007/s00401-018-1915-y
关键词
Superoxide dismutase; Prion-like; Aggregation; Propagation; Motor neuron disease
资金
- Swedish Research Council
- Knut and Alice Wallenberg Foundation
- Bertil Hallsten Foundation
- Torsten and Ragnar Soderberg Foundation
- Swedish Brain Fund
- Stratneuro Initiative
- Vasterbotten County Council
- Kempe Foundations
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 hSOD1(G127Gfs*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 hSOD1(G127Gfs*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 hSOD1(G127Gfs*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.
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