Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis–like disease
Elaheh Ekhtiari Bidhendi, … , Stefan L. Marklund, Thomas Brännström
Elaheh Ekhtiari Bidhendi, … , Stefan L. Marklund, Thomas Brännström
Published May 3, 2016
Citation Information: J Clin Invest. 2016;126(6):2249-2253. https://doi.org/10.1172/JCI84360.
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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.