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 3

Propagation of hSOD1 aggregation along the neuraxis.

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Propagation of hSOD1 aggregation along the neuraxis. (A and B) Strain A–...
(A and B) Strain A–inoculated mice. (A) Results for presymptomatic mice aged 16–47 days (n = 8). Individual mice in different colors; open and closed triangles show the left (inoculation) and right sides, respectively. In some cases (white triangles and black triangles), only 1 of the sides was available. (B) Light blue and dark blue Xs indicate the left and right sides of 3 early-onset mice, respectively. Light blue circles and dark blue circles indicate the left and right sides of terminally ill mice. (C) Terminally ill noninoculated mice (gray circles) and control-inoculated mice (green circles). (D–F) Strain B–inoculated mice. (D) Presymptomatic mice aged 25–103 days (n = 8); symbols as in A. (E) Red Xs and brown Xs indicate the left and right sides of 2 early-symptomatic 87- and 114-day-old mice, respectively. (F) Red circles and brown circles indicate the left and right sides of terminally ill mice. Shaded areas in A, B, and D indicate blank reactions (9).