| 1. |
- Gispert, Suzana, et al.
(författare)
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The modulation of Amyotrophic Lateral Sclerosis risk by Ataxin-2 intermediate polyglutamine expansions is a specific effect
- 2012
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Ingår i: Neurobiology of Disease. - : Elsevier. - 0969-9961 .- 1095-953X. ; 45:1, s. 356-361
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Tidskriftsartikel (refereegranskat)abstract
- Full expansions of the polyglutamine domain (polyQ >= 34) within the polysome-associated protein ataxin-2 (ATXN2) are the cause of a multi-system neurodegenerative disorder, which usually presents as a Spino-Cerebellar Ataxia and is therefore known as SCA2, but may rarely manifest as Levodopa-responsive Parkinson syndrome or as motor neuron disease. Intermediate expansions (27 <= polyQ <= 33) were reported to modify the risk of Amyotrophic Lateral Sclerosis (ALS). We have now tested the reproducibility and the specificity of this observation. In 559 independent ALS patients from Central Europe, the association of ATXN2 expansions (30 <= polyQ <= 35) with ALS was highly significant. The study of 1490 patients with Parkinson's disease (PD) showed an enrichment of ATXN2 alleles 27/28 in a subgroup with familial cases, but the overall risk of sporadic PD was unchanged. No association was found between polyQ expansions in Ataxin-3 (ATXN3) and ALS risk. These data indicate a specific interaction between ATXN2 expansions and the causes of ALS, possibly through altered RNA-processing as a common pathogenic factor. (C) 2011 Elsevier Inc. All rights reserved.
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| 2. |
- Jonsson, Andreas P., et al.
(författare)
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CuZn-superoxide dismutase in D90A heterozygotes from recessive and dominant ALS pedigrees
- 2002
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Ingår i: Neurobiology of Disease. - : Academic Press. - 0969-9961 .- 1095-953X. ; 10:3, s. 327-333
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in CuZn-superoxide dismutase (CuZn-SOD) have been linked to ALS. In most cases ALS is inherited as a dominant trait and there is marked reduction in CuZn-SOD activity in samples from the patients. The D90A mutation, however, mostly causes ALS as a recessive trait and shows near normal CuZn-SOD activity. A few familial and sporadic ALS cases heterozygous for the D90A mutation have also been found. Haplotype analysis of both types of D90A families has suggested that all recessive cases share a common founder and may carry a protective factor located close to the D90A mutant CuZn-SOD locus. To search for effects of a putative protective factor we analysed erythrocytes from D90A heterozygous individuals for SOD activity by a direct assay, subunit composition by immunoblotting, and zymogram pattern formed by isoelectric focusing and SOD staining. Included were heterozygotes from 17 recessive families, and from 2 dominant families and 4 apparently sporadic cases. The CuZn-SOD activity in the recessive and dominant groups was found to be equal, and 95% of controls. The ratio between mutant and wildtype subunits was likewise equal and 0.8:1 in both groups. The zymograms revealed multiple bands representing homo- and heterodimers. There were, however, no differences between the groups in patterns or in ratios between the molecular forms. In conclusion we find no evidence from analyses in erythrocytes that the putative protective factor in recessive families acts by simply downregulating the synthesis or altering the molecular structure or turnover of the mutant enzyme.
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| 3. |
- Jonsson, P Andreas, et al.
(författare)
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Superoxide dismutase in amyotrophic lateral sclerosis patients homozygous for the D90A mutation
- 2009
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961 .- 1095-953X. ; 36:3, s. 421-424
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Tidskriftsartikel (refereegranskat)abstract
- The most common of the amyotrophic lateral sclerosis (ALS)-associated superoxide dismutase-1 (SOD1) mutations, D90A, differs from others in its high structural stability and by the existence of both recessive and dominant inheritance. Here SOD1 in CNS and peripheral organs from five ALS patients homozygous for D90A were compared to controls. In most areas, including ventral horns, there were no significant differences in SOD1 activities and Western blotting patterns between controls and D90A cases. The SOD1 activities in areas vulnerable to mutant SOD1s, ventral horns and precentral gyrus were intermediate among CNS areas and much lower than in kidney and liver. Thus, the vulnerability of motor areas is not explained by high SOD1 content. The findings argue against the idea of expression-reducing protective factors being present near the D90A locus in recessive pedigrees. The similarity to wild-type SOD1 prompts speculations on the involvement of the latter in sporadic ALS.
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