superoxide dismutase 1 and tgsod1g93a mouse spinal cord seed fibrils, suggesting a propagative cell death mechanism in amyotrophic lateral sclerosis超氧化物歧化酶1和tgsod1g93a小鼠脊髓种子纤维,建议在肌萎缩性脊髓侧索硬化症繁殖的细胞死亡的机制.pdfVIP

Superoxide Dismutase 1 and tgSOD1G93A Mouse Spinal Cord Seed Fibrils, Suggesting a Propagative Cell Death Mechanism in Amyotrophic Lateral Sclerosis 1 2 2 1,2 1 Ruth Chia , M. Howard Tattum , Samantha Jones , John Collinge , Elizabeth M. C. Fisher *, Graham S. Jackson2 1 Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom, 2 MRC Prion Unit, University College London Institute of Neurology, London, United Kingdom Abstract 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 phen