Initiation and elongation in fibrillation of ALS-linked superoxide dismutase
Open Access
- 2 December 2008
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 105 (48), 18663-18668
- https://doi.org/10.1073/pnas.0807058105
Abstract
Familial amyotrophic lateral sclerosis (fALS) caused by mutations in copper–zinc superoxide dismutase (SOD1) is characterized by the presence of SOD1-rich inclusions in spinal cords. Similar inclusions observed in fALS transgenic mice have a fibrillar appearance suggestive of amyloid structure. Metal-free apo-SOD1 is a relatively stable protein and has been shown to form amyloid fibers in vitro only when it has been subjected to severely destabilizing conditions, such as low pH or reduction of its disulfide bonds. Here, by contrast, we show that a small amount of disulfide-reduced apo-SOD1 can rapidly initiate fibrillation of this exceptionally stable and highly structured protein under mild, physiologically accessible conditions, thus providing an unusual demonstration of a specific, physiologically relevant form of a protein acting as an initiating agent for the fibrillation of another form of the same protein. We also show that, once initiated, elongation can proceed via recruitment of either apo- or partially metallated disulfide-intact SOD1 and that the presence of copper, but not zinc, ions inhibits fibrillation. Our findings provide a rare glimpse into the specific changes in a protein that can lead to nucleation and into the ability of amyloid nuclei to recruit diverse forms of the same protein into fibrils.This publication has 36 references indexed in Scilit:
- Complete Loss of Post-translational Modifications Triggers Fibrillar Aggregation of SOD1 in the Familial Form of Amyotrophic Lateral SclerosisOnline Journal of Public Health Informatics, 2008
- A Limited Role for Disulfide Cross-linking in the Aggregation of Mutant SOD1 Linked to Familial Amyotrophic Lateral SclerosisOnline Journal of Public Health Informatics, 2008
- Detergent-insoluble Aggregates Associated with Amyotrophic Lateral Sclerosis in Transgenic Mice Contain Primarily Full-length, Unmodified Superoxide Dismutase-1Online Journal of Public Health Informatics, 2008
- Soluble misfolded subfractions of mutant superoxide dismutase-1s are enriched in spinal cords throughout life in murine ALS modelsProceedings of the National Academy of Sciences of the United States of America, 2007
- Metal-free superoxide dismutase forms soluble oligomers under physiological conditions: A possible general mechanism for familial ALSProceedings of the National Academy of Sciences of the United States of America, 2007
- Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model miceProceedings of the National Academy of Sciences of the United States of America, 2006
- Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondriaProceedings of the National Academy of Sciences of the United States of America, 2006
- COPPER-ZINC SUPEROXIDE DISMUTASE AND AMYOTROPHIC LATERAL SCLEROSISAnnual Review of Biochemistry, 2005
- On the nucleation of amyloid β‐protein monomer foldingProtein Science, 2005
- The Unusually Stable Quaternary Structure of Human Cu,Zn-Superoxide Dismutase 1 Is Controlled by Both Metal Occupancy and Disulfide StatusOnline Journal of Public Health Informatics, 2004