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- Jonsson, Andreas P., et al.
(author)
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Minute quantities of misfolded mutant superoxide dismutase-1 cause amyotrophic lateral sclerosis
- 2004
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In: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 127:Pt 1, s. 73-88
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Journal article (peer-reviewed)abstract
- Mutant forms of superoxide dismutase-1 (SOD1) cause amyotrophic lateral sclerosis (ALS) by an unknown noxious mechanism. Using an antibody against a novel epitope in the G127insTGGG mutation, mutant SOD1 was studied for the first time in spinal cord and brain of an ALS patient. The level was below 0.5% of the SOD1 level in controls. In corresponding transgenic mice the content of mutant SOD1 was also low, although it was enriched in spinal cord and brain compared with other tissues. In the mice the misfolded mutant SOD1 aggregated rapidly and 20% occurred in steady state as detergent-soluble protoaggregates. The misfolded SOD1 and the protoaggregates form, from birth until death, a potentially noxious burden that may induce the motor neuron injury. Detergent-resistant aggregates, as well as inclusions of mutant SOD1 in motor neurons and astrocytes, accumulated in spinal cord ventral horns of the patient and mice with terminal disease. The inclusions and aggregates may serve as terminal markers of long-term assault by misfolded SOD1 and protoaggregates.
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- Kadi, Fawzi, et al.
(author)
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The effects of heavy resistance training and detraining on satellite cells in human skeletal muscles
- 2004
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In: Journal of Physiology. - : Wiley. - 0022-3751 .- 1469-7793. ; 558:Pt 3, s. 1005-1012
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Journal article (peer-reviewed)abstract
- The aim of this study was to investigate the modulation of satellite cell content and myonuclear number following 30 and 90 days of resistance training and 3, 10, 30, 60 and 90 days of detraining. Muscle biopsies were obtained from the vastus lateralis of 15 young men (mean age: 24 years; range: 20-32 years). Satellite cells and myonuclei were studied on muscle cross-sections stained with a monoclonal antibody against CD56 and counterstained with Mayer's haematoxylin. Cell cycle markers CyclinD1 and p21 mRNA levels were determined by Northern blotting. Satellite cell content increased by 19% (P= 0.02) at 30 days and by 31% (P= 0.0003) at 90 days of training. Compared to pre-training values, the number of satellite cells remained significantly elevated at 3, 10 and 60 days but not at 90 days of detraining. The two cell cycle markers CyclinD1 and p21 mRNA significantly increased at 30 days of training. At 90 days of training, p21 was still elevated whereas CyclinD1 returned to pre-training values. In the detraining period, p21 and CyclinD1 levels were similar to the pre-training values. There were no significant alterations in the number of myonuclei following the training and the detraining periods. The fibre area controlled by each myonucleus gradually increased throughout the training period and returned to pre-training values during detraining. In conclusion, these results demonstrate the high plasticity of satellite cells in response to training and detraining stimuli and clearly show that moderate changes in the size of skeletal muscle fibres can be achieved without the addition of new myonuclei.
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5. |
- Ardeberg, Arne, et al.
(author)
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Clusters as probes of distance, evolution, and chemistry of galaxies
- 2003
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In: Proceedings of the SPIE - The International Society for Optical Engineering. - : SPIE. - 1996-756X .- 0277-786X. ; 5382:1, s. 47-56
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Conference paper (peer-reviewed)abstract
- Stellar clusters are highly useful as tools for determination of distances, ages and abundances of heavy elements of galaxies, also at larger distances. Their utility for these purposes has, so far, been severely limited, mainly due to image crowding. The introduction of Extremely Large Telescopes (ELTs) with full adaptive optics (AO) and near diffraction limited performance should imply a drastic improvement concerning the usefulness of clusters and the limiting distances of high quality data. We have made a study of stellar clusters as probes of distance, evolution and chemistry of galaxies at distances from one to twenty Mpc. From data on the Stromgren uvby system, partly from direct measurements taken from the literature, we have synthesized test clusters, one open and one globular, as well as galactic backgrounds. The clusters have been embedded in the backgrounds and located at distances between one and twenty Mpc. Here, vby data have been measured, reduced and analyzed. Color-magnitude diagrams (CMDs), metallicity diagrams (MDs) and luminosity functions (LFs) have been constructed. They have been evaluated absolutely and compared to the corresponding template data. We conclude that with a 50 m AO ELT, for open as well as globular clusters, MDs are of high quality for clusters out to and beyond 5 Mpc and useful out to 10 Mpc. CMDs are of very high quality well beyond 5 Mpc. They are of high scientific value out to and beyond 10 Mpc and valuable for clusters even out to 20 Mpc. LFs are highly informative well beyond 10 Mpc and still rather valuable at 20 Mpc. With sufficient measurement data available, LFs are useful for clusters in galaxies even beyond 20 Mpc
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8. |
- Jacobsson, Johan, et al.
(author)
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Superoxide dismutase in CSF from amyotrophic lateral sclerosis patients with and without CuZn-superoxide dismutase mutations
- 2001
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In: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 124:7, s. 1461-1466
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Journal article (peer-reviewed)abstract
- Mutations in CuZn-superoxide dismutase (CuZn-SOD) have been linked to familial amyotrophic lateral sclerosis (ALS), and motor neurone death is caused by the gain of a toxic property of the mutant protein. Here we determined amounts, activity and molecular forms of CuZn-SOD in CSF from ALS patients carrying the D90A and other CuZn-SOD mutations and patients without such mutations. There were no differences in amount of protein and enzymic activities of CuZn-SOD between 37 neurological controls, 54 sporadic and 12 familial ALS cases, and 10 cases homozygous for the D90A mutation. Three cases heterozygous for the A89V, S105L and G114A CuZn-SOD mutations showed low amounts of CuZn-SOD. There was no evidence for accumulation of inactive protein in any of the groups. Immunoblots showed no evidence for the presence of any precipitates or other molecular forms of CuZn-SOD with higher molecular weight in the groups. About 25% of the CuZn-SOD subunits in CSF from controls shows an N-terminal truncation. This truncated portion does not differ between controls and ALS groups not carrying CuZn-SOD mutations, but is 70% larger in samples from D90A homozygous ALS patients. The findings suggest an essentially normal amount and activity of D90A mutant CuZn-SOD in CNS tissues of ALS cases. The increased occurrence of N-terminally truncated mutant subunits may indicate a difference in degradation routes compared with the wild-type enzyme, resistance against subsequent proteolytic steps and/or a compromised downstream proteolytic machinery. Molecular fragments accumulated to a greater extent from the D90A mutant enzyme might contribute to the motor neurone degeneration. We also determined the other SOD isoenzymes: in the controls, CuZn-SOD contributed 75%, extracellular SOD 25% and Mn-SOD <5% of the total SOD activity. There was no difference in the amount of extracellular SOD between any of the groups.
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9. |
- Jonsson, Andreas P., et al.
(author)
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CuZn-superoxide dismutase in D90A heterozygotes from recessive and dominant ALS pedigrees
- 2002
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In: Neurobiology of Disease. - : Academic Press. - 0969-9961 .- 1095-953X. ; 10:3, s. 327-333
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Journal article (peer-reviewed)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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- Liu, Jian, et al.
(author)
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Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria
- 2004
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In: Neuron. - : Cell Press. - 0896-6273 .- 1097-4199. ; 43:1, s. 5-17
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Journal article (peer-reviewed)abstract
- One cause of amyotrophic lateral sclerosis (ALS) is mutation in ubiquitously expressed copper/zinc superoxide dismutase (SOD1), but the mechanism of toxicity to motor neurons is unknown. Multiple disease-causing mutants, but not wild-type SOD1, are now demonstrated to be recruited to mitochondria, but only in affected tissues. This is independent of the copper chaperone for SOD1 and dismutase activity. Highly preferential association with spinal cord mitochondria is seen in human ALS for a mutant SOD1 that accumulates only to trace cytoplasmic levels. Despite variable proportions that are successfully imported, nearly constant amounts of SOD1 mutants and covalently damaged adducts of them accumulate as apparent import intermediates and/or are tightly aggregated or crosslinked onto integral membrane components on the cytoplasmic face of those mitochondria. These findings implicate damage from action of spinal cord-specific factors that recruit mutant SOD1 to spinal mitochondria as the basis for their selective toxicity in ALS.
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