Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes

Andersen, Peter M.; Sims, Katherine B.; Xin, Winnie; Kiely, Rosemary; O’Neill, Gilmore; Ravits, John; Pioro, Erik P.; Harati, Yadollah; Brower, Richard; Levine, Johanan S; Heinicke, Hedvika U.; Seltzer, William; Boss, Michael A.; Brown, Robert H.

doi:10.1080/14660820310011700

Cited by 240 publications

(140 citation statements)

References 18 publications

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“…Approximately 10% of ALS cases are familial (1) and in some of these the disease is linked to mutations in the CuZn-superoxide dismutase (SOD1) gene (2). Overall, Ϸ6% of all cases with ALS show SOD1 mutations, and more than 100 different such mutations have been identified (3). The mutations confer a cytotoxic gain of function to the enzyme (4,5).…”

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confidence: 99%

Soluble misfolded subfractions of mutant superoxide dismutase-1s are enriched in spinal cords throughout life in murine ALS models

Zetterström

Stewart

Bergemalm

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

142

156

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Mutants of superoxide dismutase-1 (SOD1) cause ALS by an unidentified cytotoxic mechanism. We have previously shown that the stable SOD1 mutants D90A and G93A are abundant and show the highest levels in liver and kidney in transgenic murine ALS models, whereas the unstable G85R and G127X mutants are scarce but enriched in the CNS. These data indicated that minute amounts of misfolded SOD1 enriched in the motor areas might exert the ALS-causing cytotoxicity. A hydrophobic interaction chromatography (HIC) protocol was developed with the aim to determine the abundance of soluble misfolded SOD1 in tissues in vivo. Most G85R and G127X mutant SOD1s bound in the assay, but only minute subfractions of the D90A and G93A mutants. The absolute levels of HIC-binding SOD1 were, however, similar and broadly inversely related to lifespans in the models. They were generally enriched in the susceptible spinal cord. The HIC-binding SOD1 was composed of disulfide-reduced subunits lacking metal ions and also subunits that apparently carried nonnative intrasubunit disulfide bonds. The levels were high from birth until death and were comparable to the amounts of SOD1 that become sequestered in aggregates in the terminal stage. The HIC-binding SOD1 species ranged from monomeric to trimeric in size. These species form a least common denominator amongst SOD1 mutants with widely different molecular characteristics and might be involved in the cytotoxicity that causes ALS.disulfide bond ͉ motor neuron ͉ neurodegeneration A myotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration, resulting in progressive paralysis, and death from respiratory failure. Approximately 10% of ALS cases are familial (1) and in some of these the disease is linked to mutations in the CuZn-superoxide dismutase (SOD1) gene (2). Overall, Ϸ6% of all cases with ALS show SOD1 mutations, and more than 100 different such mutations have been identified (3). The mutations confer a cytotoxic gain of function to the enzyme (4, 5). SOD1 is ubiquitously expressed, and in several organs at higher levels than in the motor areas in the CNS (6, 7). Both the nature of the cytotoxicity, and the reasons for the particular susceptibility of some parts of the CNS remain unexplained.It is likely that the different mutant SOD1s cause ALS by essentially the same mechanism. Still, the levels of different mutant SOD1s in the human CNS differ by more than 200-fold (7). Similar large differences are observed in the murine ALS models. In spinal cords from mice expressing the D90A, G93A, G85R and G127insTGGG (G127X) mutant human SOD1s (hSOD1s), the levels are 20, 14, 0.9, and 0.45 times as large, respectively, as the levels of the endogenous murine SOD1 (mSOD1) (8). In the high-level models, D90A and G93A, most hSOD1 lacks enzymatic activity owing to Cu-deficiency, and significant proportions lack the stabilizing intrasubunit disulfide bond. The G85R and G127X hSOD1s lack both enzymatic activity and the disulfide bond. Whereas the liver and kidney contain the highest lev...

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confidence: 99%

Soluble misfolded subfractions of mutant superoxide dismutase-1s are enriched in spinal cords throughout life in murine ALS models

Zetterström

Stewart

Bergemalm

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

142

156

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“…The motor-neuron disorder amyotrophic lateral sclerosis (ALS) 2 has been associated to more than 100 missense mutations in the radical scavenger copper/zinc superoxide dismutase (SOD1) (1). In analogy with several other neurodegenerative disorders (2), ALS seems associated with protein misfolding and aggregation (3)(4)(5)(6)(7)(8).…”

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confidence: 99%

Amyotrophic Lateral Sclerosis-associated Copper/Zinc Superoxide Dismutase Mutations Preferentially Reduce the Repulsive Charge of the Proteins

Sandelin

Nordlund

Andersen

et al. 2007

Journal of Biological Chemistry

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We provide bioinformatical evidence that protein charge plays a key role in the disease mechanism of amyotrophic lateral sclerosis (ALS). Analysis of 100 ALS-associated mutations in copper/zinc superoxide dismutase (SOD1) shows that these are site-selective with a preference to decrease the proteins' net repulsive charge. For each SOD1 monomer this charge is normally ؊6. Because biomolecules as a rule maintain net negative charge to assure solubility in the cellular interior, the result lends support to the hypothesis of protein aggregation as an initiating event in the ALS pathogenesis. The strength of the preferential reduction of repulsive charge is higher in SOD1-associated ALS than in other inherited protein disorders.The motor-neuron disorder amyotrophic lateral sclerosis (ALS) 2 has been associated to more than 100 missense mutations in the radical scavenger copper/zinc superoxide dismutase (SOD1) (1). In analogy with several other neurodegenerative disorders (2), ALS seems associated with protein misfolding and aggregation (3-8). The principal support for such a disease mechanism is that the neural damage is accompanied by the accumulation of intracellular SOD1 deposits (9, 10). Even so, it is not the mature protein inclusions that seem to pose the main problem but rather some yet unidentified precursor accumulating in connection to the macroscopic aggregation process (11)(12)(13)(14)(15)(16). Consistent with such a scenario, transgenic mice suffer neuron stress long before any SOD1 inclusions can be detected (10,17,18). At the molecular level, studies of how the individual ALS-associated mutations affect the SOD1 molecule have further indicated protein stability as an important factor in the disease mechanism (19 -25); the more severe the destabilization caused by the mutation, the faster the disease progression (20). In this study, we shed further light on the disease-provoking properties of the SOD1 molecule by examining bioinformatically the chemical nature of 100 ALS-associated missense mutations. The results reveal an additional disease factor; the mutations have an overall tendency to decrease the net negative charge of the proteins. The negative charge repulsion that generally assures macromolecular solubility in vivo is diminished. This tendency is stronger for ALS mutations than in other hereditary protein disorders and cannot be discerned in the interspecies variability of the SOD1 sequence. In the few contrasting cases where the SOD1 mutations produce an increased repulsive charge, the side chain substitution tends also to be structurally obstructive and to occur in strictly conserved positions. That is, the opposed effect of increased repulsive charge is not sufficiently strong to compensate for the accompanying penalties in protein stability. The observation shows that the decreased net negative charge of SOD1 is a critical contributory factor to the ability of the mutation to cause neural damage. Taken together with the impact of decreased protein stability, the data also provide genetic s...

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“…The most common genetic abnormalities leading to fALS are dominant mutations in superoxide dismutase 1 (SOD1), with over 100 mutations identified to date (3). SOD1 has therefore been extensively studied, and a mouse model of SOD1-induced ALS is the major tool used to test potential therapeutics (4).…”

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confidence: 99%

“…One such disease is amyotrophic lateral sclerosis (ALS), 3 which targets spinal motor neurons that control voluntary movement. ALS carries a cumulative lifetime risk of 1 in 1,000 and is fatal, leading to respiratory failure within 3-5 years (2).…”

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confidence: 99%

Ubiquilin Modifies TDP-43 Toxicity in a Drosophila Model of Amyotrophic Lateral Sclerosis (ALS)

Hanson¹,

Kim

Wassarman

et al. 2010

Journal of Biological Chemistry

118

107

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Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes

Cited by 240 publications

References 18 publications

Soluble misfolded subfractions of mutant superoxide dismutase-1s are enriched in spinal cords throughout life in murine ALS models

Soluble misfolded subfractions of mutant superoxide dismutase-1s are enriched in spinal cords throughout life in murine ALS models

Amyotrophic Lateral Sclerosis-associated Copper/Zinc Superoxide Dismutase Mutations Preferentially Reduce the Repulsive Charge of the Proteins

Ubiquilin Modifies TDP-43 Toxicity in a Drosophila Model of Amyotrophic Lateral Sclerosis (ALS)

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