Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis–like disease
Elaheh Ekhtiari Bidhendi, Johan Bergh, Per Zetterström, Peter M. Andersen, Stefan L. Marklund, Thomas Brännström
Elaheh Ekhtiari Bidhendi, Johan Bergh, Per Zetterström, Peter M. Andersen, Stefan L. Marklund, Thomas Brännström
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Concise Communication Neuroscience

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

Elaheh Ekhtiari Bidhendi, Johan Bergh, Per Zetterström, Peter M. Andersen, Stefan L. Marklund, Thomas Brännström

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Figure 1

Epitope-mapping patterns of seeds and aggregates formed in inoculated mice.

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Epitope-mapping patterns of seeds and aggregates formed in inoculated mi...
(A) Epitope-mapping patterns of the strain A seed (analyzed on 4 different occasions to demonstrate the method’s variability), 4 terminally ill strain A–inoculated mice, and 4 terminally ill noninoculated hSOD1G85R-Tg mice. The staining intensities with the 8 Abs were normalized against staining with the aa 57–72 Ab (set to 100%) to facilitate the comparison of patterns. (B) Patterns of the strain B seed (analyzed on 5 different occasions) and of 11 terminally ill strain B–inoculated hSOD1G85R-Tg mice. The staining intensities were normalized against staining with the aa 111–127 Ab (set to 100%). Typical strain B patterns are seen. (C) Strain A aggregate deposition in spinal cord of a hSOD1G85R mouse sacrificed 24 hours after the inoculation. The section was stained with the aa 131–153 Ab. No such staining was induced by a syringe stick alone (Supplemental Figure 4). Arrow indicates the position of the seed in the left side of the lumbar spinal cord. cc, central channel. Scale bar: 50 μm. Dotted line delineates the ventral horn.