Abstract
BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that specifically affects motor neurons and leads to a progressive and ultimately fatal loss of function, resulting in death typically within 3 to 5 years of diagnosis. The disease starts with a focal centre of weakness, such as one limb, and appears to spread to other parts of the body. Mutations in superoxide dismutase 1 (SOD1) are known to cause disease and it is generally accepted they lead to pathology not by loss of enzymatic activity but by gain of some unknown toxic function(s). Although different mutations lead to varying tendencies of SOD1 to aggregate, we suggest abnormal proteins share a common misfolding pathway that leads to the formation of amyloid fibrils.Methodology/Principal FindingsHere we demonstrate that misfolding of superoxide dismutase 1 leads to the formation of amyloid fibrils associated with seeding activity, which can accelerate the formation of new fibrils in an autocatalytic cascade. The time limiting event is nucleation to form a stable protein “seed” before a rapid linear polymerisation results in amyloid fibrils analogous to other protein misfolding disorders. This phenomenon was not confined to fibrils of recombinant protein as here we show, for the first time, that spinal cord homogenates obtained from a transgenic mouse model that overexpresses mutant human superoxide dismutase 1 (the TgSOD1G93A mouse) also contain amyloid seeds that accelerate the formation of new fibrils in both wildtype and mutant SOD1 protein in vitro.Conclusions/SignificanceThese findings provide new insights into ALS disease mechanism and in particular a mechanism that could account for the spread of pathology throughout the nervous system. This model of disease spread, which has analogies to other protein misfolding disorders such as prion disease, also suggests it may be possible to design assays for therapeutics that can inhibit fibril propagation and hence, possibly, disease progression.
Highlights
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease defined by the selective death of upper and lower motor neurons [1,2]
superoxide dismutase 1 (SOD1) fibrillization assays with varying solvent conditions were undertaken and we showed in vitro that misfolding of SOD1 protein leads to the formation of amyloid fibrils which can seed the formation of further fibrils in an autocatalytic cascade
To screen and select for a condition which would be conducive for SOD1 to form oligomers and amyloid-like fibrils, human SOD1 proteins – wildtype SOD1 and four fALS causative mutations, G93A, G37R, A4V, and G85R, were incubated in a matrix of 28 varying solvent conditions, totalling 140 screened conditions for all five proteins studied
Summary
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease defined by the selective death of upper and lower motor neurons [1,2]. SOD1 mutations are known to be causative in 10–20% fALS cases, and have been observed in 2% sporadic cases [1]. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons and leads to a progressive and fatal loss of function, resulting in death typically within 3 to 5 years of diagnosis. Mutations in superoxide dismutase 1 (SOD1) are known to cause disease and it is generally accepted they lead to pathology not by loss of enzymatic activity but by gain of some unknown toxic function(s). Different mutations lead to varying tendencies of SOD1 to aggregate, we suggest abnormal proteins share a common misfolding pathway that leads to the formation of amyloid fibrils
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