SOD1-positive aggregate accumulation in the CNS predicts slower disease progression and increased longevity in a mutant SOD1 mouse model of ALS

Cindy Gill,Kenneth Thompson,Theo Hatzipetros,Andrew Moreno,Alan Gill,Valerie R Tassinari,James P Phelan,Fernando G Vieira,Marcel Maier,Monica Z Wang,Jan Grimm,Beth Levine,Joshua D Kidd

doi:10.1038/s41598-019-43164-z

Abstract

Non-natively folded variants of superoxide dismutase 1 (SOD1) are thought to contribute to the pathogenesis of familial amyotrophic lateral sclerosis (ALS), however the relative toxicities of these variants are controversial. Here, we aimed to decipher the relationships between the different SOD1 variants (aggregated, soluble misfolded, soluble total) and the clinical presentation of ALS in the SOD1G93A mouse. Using a multi-approach strategy, we found that the CNS regions least affected by disease had the most aggregated SOD1. We also found that the levels of aggregated SOD1 in the spinal cord were inversely correlated with the disease progression. Conversely, in the most affected regions, we observed that there was a high soluble misfolded/soluble total SOD1 ratio. Taken together, these findings suggest that soluble misfolded SOD1 may be the disease driver in ALS, whereas aggregated SOD1 may serve to sequester the toxic species acting in a neuroprotective fashion.

Highlights

Non-natively folded variants of superoxide dismutase 1 (SOD1) are thought to contribute to the pathogenesis of familial amyotrophic lateral sclerosis (ALS), the relative toxicities of these variants are controversial
ALS can be classified into two categories: familial ALS (FALS) and sporadic ALS (SALS) which account for approximately 10% and 90% of ALS cases, respectively[2]
Lumbar spinal cord was the focus of these studies because this is the region of the central nervous system with which clinical symptoms of SOD1G93A mice are most closely associated[23]

Summary

Introduction

Non-natively folded variants of superoxide dismutase 1 (SOD1) are thought to contribute to the pathogenesis of familial amyotrophic lateral sclerosis (ALS), the relative toxicities of these variants are controversial. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by dysfunction and degeneration of lower motor neurons in the spinal cord and brain stem and upper motor neurons in the motor cortex[1,2] When these neurons fail, the affected person experiences fasciculations, spasticity, weakness, muscle atrophy, and fatal paralysis[1]. SOD1 is an anti-oxidant enzyme that catalyzes the dismutation of superoxide radicals[6] Both normal and mutated SOD1 exhibit physical characteristics that increase the likelihood of unfolding, misfolding, polymerization, aggregation, loss of function, and toxic gain of function[7,8,9,10,11,12,13,14,15,16,17]. Understanding of the physicochemical properties of wild-type human SOD1 and its various mutations has continually improved since its identification as an ALS-causative risk factor, how SOD1 mutations www.nature.com/scientificreports/

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