title: Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis-like disease.
abstract: Amyotrophic lateral sclerosis (ALS) is an adult-onset degeneration of motor neurons that is commonly caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Both patients and Tg mice expressing mutant human SOD1 (hSOD1) develop aggregates of unknown importance. In Tg mice, 2 different strains of hSOD1 aggregates (denoted A and B) can arise; however, the role of these aggregates in disease pathogenesis has not been fully characterized. Here, minute amounts of strain A and B hSOD1 aggregate seeds that were prepared by centrifugation through a density cushion were inoculated into lumbar spinal cords of 100-day-old mice carrying a human SOD1 Tg. Mice seeded with A or B aggregates developed premature signs of ALS and became terminally ill after approximately 100 days, which is 200 days earlier than for mice that had not been inoculated or were given a control preparation. Concomitantly, exponentially growing strain A and B hSOD1 aggregations propagated rostrally throughout the spinal cord and brainstem. The phenotypes provoked by the A and B strains differed regarding progression rates, distribution, end-stage aggregate levels, and histopathology. Together, our data indicate that the aggregate strains are prions that transmit a templated, spreading aggregation of hSOD1, resulting in a fatal ALS-like disease.
authors.forename: Elaheh Ekhtiari
authors.initials: EE
authors.lastname: Bidhendi
authors.forename: Johan
authors.initials: J
authors.lastname: Bergh
authors.forename: Per
authors.initials: P
authors.lastname: Zetterström
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.forename: Stefan L
authors.initials: SL
authors.lastname: Marklund
authors.forename: Thomas
authors.initials: T
authors.lastname: Brännström
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics*; D011328:Prions / Q000737:chemistry / Q000235:genetics*; D066329:Protein Aggregates / Q000235:genetics; D066263:Protein Aggregation, Pathological / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D000072105:Superoxide Dismutase-1 / Q000737:chemistry / Q000235:genetics*
chemical_list: D050505:Mutant Proteins; D011328:Prions; D066329:Protein Aggregates; D011994:Recombinant Proteins; C000606290:SOD1 protein, human; D000072105:Superoxide Dismutase-1