ALSOD: The Amyotrophic Lateral Sclerosis Online Database

Wroe, Richard; Butler, Amy W.; Andersen, Peter M.; Powell, John; Al‐Chalabi, Ammar

doi:10.1080/17482960802146106

Cited by 134 publications

(86 citation statements)

References 1 publication

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“…Overall, about 6% of all cases with ALS show SOD1 mutations, and more than 160 such mutations have been identified (2). The mutations confer a cytotoxic gain of function of unknown character to the enzyme (3)(4).…”

Section: Amyotrophic Lateral Sclerosis (Als)mentioning

confidence: 99%

Proteins That Bind to Misfolded Mutant Superoxide Dismutase-1 in Spinal Cords from Transgenic Amyotrophic Lateral Sclerosis (ALS) Model Mice

Zetterström

Graffmo

Andersen

et al. 2011

Journal of Biological Chemistry

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Mutant superoxide dismutase-1 (SOD1) has an unidentified toxic property that provokes ALS. Several ALS-linked SOD1 mutations cause long C-terminal truncations, which suggests that common cytotoxic SOD1 conformational species should be misfolded and that the C-terminal end cannot be involved. The cytotoxicity may arise from interaction of cellular proteins with misfolded SOD1 species. Here we specifically immunocaptured misfolded SOD1 by the C-terminal end, from extracts of spinal cords from transgenic ALS model mice. Associated proteins were identified with proteomic techniques. Two transgenic models expressing SOD1s with contrasting molecular properties were examined: the stable G93A mutant, which is abundant in the spinal cord with only a tiny subfraction misfolded, and the scarce disordered truncation mutant G127insTGGG. For comparison, proteins in spinal cord extracts with affinity for immobilized apo G93A mutant SOD1 were determined. Two-dimensional gel patterns with a limited number of bound proteins were found, which were similar for the two SOD1 mutants. Apart from neurofilament light, the proteins identified were all chaperones and by far most abundant was Hsc70. The immobilized apo G93A SOD1, which would populate a variety of conformations, was found to bind to a considerable number of additional proteins. A substantial proportion of the misfolded SOD1 in the spinal cord extracts appeared to be chaperone-associated. Still, only about 1% of the Hsc70 appeared to be associated with misfolded SOD1. The results argue against the notion that chaperone depletion is involved in ALS pathogenesis in the transgenic models and in humans carrying SOD1 mutations.Amyotrophic lateral sclerosis (ALS) 2 is characterized by degeneration of motor neurons in the motor cortex, the brainstem, and the spinal cord. This results in progressive muscular atrophy and the patients usually succumb to respiratory failure within a few years. About 10% of ALS cases cluster in families (1), and in some of these the disease is linked to mutations in the gene of the antioxidant enzyme superoxide dismutase-1 (SOD1).Overall, about 6% of all cases with ALS show SOD1 mutations, and more than 160 such mutations have been identified (2). The mutations confer a cytotoxic gain of function of unknown character to the enzyme (3-4). The ALS-linked mutant SOD1s, including nine with long C-terminal truncations, are likely to cause ALS by essentially the same mechanism. In the shortest of these the native sequence ends with Leu-117 followed by four novel amino acids and a premature stop codon. The truncated mutants lack the stabilizing Cys-57-Cys-146 disulfide bond and ␤-strand 8 of the ␤-barrel core of the protein, and should show limited native folding. Thus, any cytotoxic conformational species common to the ALSlinked SOD1 mutations should be misfolded. Furthermore, the C-terminal end cannot be involved in the cytotoxicity. One conceivable mechanism by which such misfolded SOD1 species might provoke the disease is through interaction with essential...

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Section: Amyotrophic Lateral Sclerosis (Als)mentioning

confidence: 99%

Proteins That Bind to Misfolded Mutant Superoxide Dismutase-1 in Spinal Cords from Transgenic Amyotrophic Lateral Sclerosis (ALS) Model Mice

Zetterström

Graffmo

Andersen

et al. 2011

Journal of Biological Chemistry

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“…2; ref. 3 and http://alsod.iop. kcl.ac.uk/) that confer a cytotoxic gain of function on the enzyme that is still poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis–like disease

Bidhendi¹,

Bergh²,

Zetterström³

et al. 2016

Journal of Clinical Investigation

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117

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“…Mutations in several genes have now been found in familial ALS, but in every case similar mutations have been identified in a proportion of those with apparently sporadic ALS (http://alsod.iop.kcl.ac.uk [12] ). The commonest cause of familial ALS is mutation in the SOD1 gene (OMIM 147450), accounting for about 20% of familial cases [13] .…”

Section: Introductionmentioning

confidence: 99%

Modelling the Effects of Penetrance and Family Size on Rates of Sporadic and Familial Disease

Al‐Chalabi

Lewis

2011

Hum Hered

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Background/Aims: Many complex diseases show a diversity of inheritance patterns ranging from familial disease, manifesting with autosomal dominant inheritance, through to simplex families in which only one person is affected, manifesting as apparently sporadic disease. The role of ascertainment bias in generating apparent patterns of inheritance is often overlooked. We therefore explored the role of two key parameters that influence ascertainment, penetrance and family size, in rates of observed familiality. Methods: We develop a mathematical model of familiality of disease, with parameters for penetrance, mutation frequency and family size, and test this in a complex disease: amyotrophic lateral sclerosis. Results: Monogenic, high-penetrance variants can explain patterns of inheritance in complex diseases and account for a large proportion of those with no apparent family history. With current demographic trends, rates of familiality will drop further. For example, a variant with penetrance 0.5 will cause apparently sporadic disease in 12% of families of size 10, but 80% of families of size 1. A variant with penetrance 0.9 has only an 11% chance of appearing sporadic in families of a size similar to those of Ireland in the past, compared with 57% in one-child families like many in China. Conclusions: These findings have implications for genetic counselling, disease classification and the design of gene-hunting studies. The distinction between familial and apparently sporadic disease should be considered artificial.

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ALSOD: The Amyotrophic Lateral Sclerosis Online Database

Cited by 134 publications

References 1 publication

Proteins That Bind to Misfolded Mutant Superoxide Dismutase-1 in Spinal Cords from Transgenic Amyotrophic Lateral Sclerosis (ALS) Model Mice

Proteins That Bind to Misfolded Mutant Superoxide Dismutase-1 in Spinal Cords from Transgenic Amyotrophic Lateral Sclerosis (ALS) Model Mice

Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis–like disease

Modelling the Effects of Penetrance and Family Size on Rates of Sporadic and Familial Disease

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