Journal Article

Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis–like disease

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

2016

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - etiology / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Analysis / Animals / Biomedical research / Brief Report / Complications and side effects / Disease Models, Animal / Disease transmission / Histopathology / Humans / Mice / Mice, Inbred C57BL / Mice, Transgenic / Motor Neurons - metabolism / Motor Neurons - pathology / Mutant Proteins - chemistry / Mutant Proteins - genetics / Neurons / Prions - chemistry / Prions - genetics / Protein Aggregates - genetics / Protein Aggregation, Pathological - genetics / Recombinant Proteins - chemistry / Recombinant Proteins - genetics / Respiratory insufficiency / Risk factors / Seeds / Spinal cord / Spinal Cord - metabolism / Spinal Cord - pathology / Superoxide Dismutase-1 - chemistry / Superoxide Dismutase-1 - genetics