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Assay Development for High Content Quantification of Sod1 Mutant Protein Aggregate Formation in Living Cells
Published on: October 4, 2017
SOD1 and amyotrophic lateral sclerosis: mutations and oligomerization
Lucia Banci1, Ivano Bertini, Mirela Boca
1Magnetic Resonance Center (CERM), Department of Chemistry, University of Florence, Florence, Italy.
Plos One
|February 28, 2008
Summary
Familial amyotrophic lateral sclerosis (fALS) involves mutations in copper, zinc superoxide dismutase 1 (SOD1). Metal-free SOD1 mutants and wild-type protein oligomerize via oxidation, forming toxic, amyloid-like structures implicated in ALS pathogenesis.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Familial amyotrophic lateral sclerosis (fALS) is linked to over 100 mutations in copper, zinc superoxide dismutase 1 (SOD1).
- SOD1 aggregates are found in motor neurons of fALS patients and associated with mitochondria.
- Mitochondria are sites prone to oxidative stress.
Purpose of the Study:
- To investigate the aggregation propensity of eleven SOD1 mutants.
- To elucidate the mechanism of oligomerization for metal-free SOD1 and its mutants.
- To identify potential toxic species contributing to ALS.
Main Methods:
- Circular dichroism spectroscopy
- Thioflavin T (ThT)-binding fluorescence assays
- Size-exclusion chromatography
- Light scattering spectroscopy
Main Results:
- Metal-free SOD1 mutants and wild-type protein share a common oligomerization mechanism.
- Oligomerization involves cysteine oxidation and hydrogen bond stabilization, forming amyloid-like structures.
- Soluble oligomeric species, formed from apo-SOD1 via oxidation, may be toxic precursors.
Conclusions:
- The proposed oligomerization mechanism is general for SOD1 mutants, explaining diverse behaviors.
- Oxidative oligomerization of apo-SOD1 (wild-type and mutants) offers a common pathway for ALS and fALS.
- These soluble oligomers represent potential toxic species in ALS pathogenesis.
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