SOD1 and amyotrophic lateral sclerosis: mutations and oligomerization

• Published in: PloS one 2008-02, Vol.3 (2), p.e1677
• Main Authors: Banci, Lucia, Bertini, Ivano, Boca, Mirela, Girotto, Stefania, Martinelli, Manuele, Valentine, Joan Selverstone, Vieru, Miguela
• Format: Article
• Language: English
• Subjects: Amyloid; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Biochemistry; Biochemistry/Bioinorganic Chemistry; Biophysics/Protein Folding; Chemical bonds; Chromatography; Circular dichroism; Copper; Cysteine - metabolism; Dichroism; Dimerization; Disease; Enzymes; Fluorescence; Free form; Gene mutation; Genetic aspects; Humans; Hydrogen; Hydrogen Bonding; Hydrogen bonds; Kinetics; Light scattering; Metals; Mitochondria; Mitochondria - metabolism; Molecular Biology; Molecular weight; Motor neurons; Mutants; Mutation; Neurological Disorders; Oligomerization; Oligomers; Oxidation; Oxidation-Reduction; Oxidative stress; Pathology; Physiology; Protein Conformation; Proteins; Species; Spectroscopy; Superoxide dismutase; Superoxide Dismutase - chemistry; Superoxide Dismutase - genetics; Superoxide Dismutase-1; Superoxides; Transgenic animals; Zinc
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0001677

There are about 100 single point mutations of copper, zinc superoxide dismutase 1 (SOD1) which are reported (http://alsod.iop.kcl.ac.uk/Als/index.aspx) to be related to the familial form (fALS) of amyotrophic lateral sclerosis (ALS). These mutations are spread all over the protein. It is well documented that fALS produces protein aggregates in the motor neurons of fALS patients, which have been found to be associated to mitochondria. We selected eleven SOD1 mutants, most of them reported as pathological, and characterized them investigating their propensity to aggregation using different techniques, from circular dichroism spectra to ThT-binding fluorescence, size-exclusion chromatography and light scattering spectroscopy. We show here that these eleven SOD1 mutants, only when they are in the metal-free form, undergo the same general mechanism of oligomerization as found for the WT metal-free protein. The rates of oligomerization are different but eventually they give rise to the same type of soluble oligomeric species. These oligomers are formed through oxidation of the two free cysteines of SOD1 (6 and 111) and stabilized by hydrogen bonds, between beta strands, thus forming amyloid-like structures. SOD1 enters the mitochondria as demetallated and mitochondria are loci where oxidative stress may easily occur. The soluble oligomeric species, formed by the apo form of both WT SOD1 and its mutants through an oxidative process, might represent the precursor toxic species, whose existence would also suggest a common mechanism for ALS and fALS. The mechanism here proposed for SOD1 mutant oligomerization is absolutely general and it provides a common unique picture for the behaviors of the many SOD1 mutants, of different nature and distributed all over the protein.