Superoxide Dismutase 1 and tgSOD1G93A Mouse Spinal Cord Seed Fibrils, Suggesting a Propagative Cell Death Mechanism in Amyotrophic Lateral Sclerosis

被引:102
作者
Chia, Ruth [1 ]
Tattum, M. Howard [2 ]
Jones, Samantha [2 ]
Collinge, John [1 ,2 ]
Fisher, Elizabeth M. C. [1 ]
Jackson, Graham S. [2 ]
机构
[1] Univ Coll London Inst Neurol, Dept Neurodegenerat Dis, London, England
[2] Univ Coll London Inst Neurol, MRC Prion Unit, London, England
来源
PLOS ONE | 2010年 / 5卷 / 05期
基金
英国医学研究理事会;
关键词
MOTOR-NEURON DEGENERATION; BODY-LIKE INCLUSIONS; TRANSGENIC MICE; FAMILIAL ALS; INTRANUCLEAR INCLUSIONS; DISEASE PROGRESSION; SOD1; MUTATIONS; AGGREGATION; MUTANTS;
D O I
10.1371/journal.pone.0010627
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: Amyotrophic 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 Findings: Here 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 TgSOD1(G93A) mouse) also contain amyloid seeds that accelerate the formation of new fibrils in both wildtype and mutant SOD1 protein in vitro. Conclusions/Significance: These 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.
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页数:10
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