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Minute quantities of misfolded mutant superoxide dismutase-1 cause amyotrophic lateral sclerosis.
Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
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2004 (English)In: Brain, ISSN 0006-8950, Vol. 127, no Pt 1, 73-88 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2004. Vol. 127, no Pt 1, 73-88 p.
Keyword [en]
Amyotrophic Lateral Sclerosis/enzymology/*genetics, Animals, Anterior Horn Cells/enzymology, Brain/enzymology, Detergents/pharmacology, Disease Models; Animal, Female, Humans, Mice, Mice; Transgenic, Middle Aged, Mutation, Phenotype, Solubility, Spinal Cord/enzymology, Superoxide Dismutase/drug effects/*genetics/immunology/metabolism, Survival Analysis
Identifiers
URN: urn:nbn:se:umu:diva-15192DOI: 10.1093/brain/awh005PubMedID: 14534160OAI: oai:DiVA.org:umu-15192DiVA: diva2:154864
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2009-11-18Bibliographically approved
In thesis
1. Of mice and men: SOD1 associated human amyotrophic lateral sclerosis and transgenic mouse models
Open this publication in new window or tab >>Of mice and men: SOD1 associated human amyotrophic lateral sclerosis and transgenic mouse models
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Amyotrophic lateral sclerosis, ALS, is a progressive fatal neurodegenerative disorder affecting motor neurones in motor cortex, brain stem and spinal cord. This inevitably leads to paralysis, respiratory failure and death. In about 5% of patients with ALS there is an association with mutations in gene for the abundant intracellular scavenging enzyme superoxide dismutase1, SOD1. The noxious property of SOD1 is proposed to be due to gain of function. In familial cases the inheritance is most commonly dominant.

This study focus on two disparate SOD1 mutations occurring in Scandinavia. The recessive D90A mutation which has properties similar to that of the normal wild-type human SOD1. The dominantly inherited G127insTGGG mutation, G127X, causes a C-terminal truncation of the last 21 amino acids and is a highly unstable protein.

Transgenic mice were created expressing D90A and G127X mutated human SOD1. Results from studies of tissue from the central nervous system of patients carrying either of these mutations were compared with similar tissue collected from transgenic mice generated with the same mutations. Tissue from the mice were also compared to central nervous tissue from several other transgenic mouse strains expressing human wild type SOD1 as well as other ALS associated human SOD1 mutations.

The transgenic mice expressing D90A respectively G127X mutated human SOD1 develop motor neurone disease. Microscopic studies of central nervous tissues from G127X transgenic mice reveals inclusions of aggregated misfolded SOD1 in motor neurones and adjacent supporting cells. These inclusions are composed of detergent resistant aggregates and preceded by accumulations of minute quantities of detergent-soluble aggregates. The inclusions mimic those found in G127X patients.

In D90A transgenic mice the progression, as in the humans, was slower and the mice, as the patients, showed bladder disturbance. In the D90A patients, the SOD1 inclusions mimic those found in sporadic ALS patients.

Aggregation of SOD1 in central nervous tissue appears to be related to severity of disease. Degenerative features as vacuolization and gliosis precedes phenotypic alterations. Changes are seen not only in motor areas but also in higher centres of the telencephalon.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap, 2007. 74 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1118
Keyword
aggregates, ALS, amyotrophic lateral sclerosis, inclusions, misfolded, vacuolisation, SOD1, transgenic
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-1376 (URN)978-91-7264-388-8 (ISBN)
Public defence
2007-10-19, sal C, 9 tr, 1D, Tandläkarhögskolan, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2007-09-28 Created: 2007-09-28 Last updated: 2009-05-19Bibliographically approved
2. Superoxide dismutase 1 and amyotrophic lateral sclerosis
Open this publication in new window or tab >>Superoxide dismutase 1 and amyotrophic lateral sclerosis
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Superoxid dismutas 1 och amyotrofisk lateralskleros
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons in the spinal cord, brain stem and motor cortex, leading to paralysis, respiratory failure and death. In about 5% of ALS cases, the disease is associated with mutations in the CuZn-superoxide dismutase (hSOD1) gene. As a rule, ALS caused by hSOD1 mutations is inherited dominantly and the mutant hSOD1s cause ALS by the gain of a noxious property.

The present study focused on two hSOD1 mutations with widely differing characters. In Scandinavia, ALS caused by the D90A mutation is inherited in a recessive pattern. Elsewhere, families with dominant inheritance have been found. The properties of D90A mutant hSOD1 are very similar to those of the wild-type protein. The G127insTGGG (G127X) mutation causes a 21 amino acid C-terminal truncation which probably results in an unstable protein.

The aim of this thesis was to generate transgenic mice expressing D90A and G127X mutant hSOD1s and to compare these mice with each other and with mice expressing other mutant hSOD1s, in search of a common noxious property. The findings were also compared with the results from studies of human CNS tissue.

The cause of the different inheritance patterns associated with D90A mutant hSOD1 was investigated by analyzing erythrocytes from heterozygous individuals from dominant and recessive pedigrees. There was no evidence that a putative protective factor in recessive pedigrees acts by down-regulating the synthesis of D90A mutant hSOD1.

In cerebrospinal fluid, there was no difference in hSOD1 content between homozygous D90A patients, ALS patients without hSOD1 mutations and controls. hSOD1 cleaved at the N-terminal end was found in both controls and D90A patients, but the proportion was significantly larger in the latter group. This indicates a difference in degradation routes between mutant and wild-type hSOD1.

Both D90A and G127X transgenic mice develop an ALS-like phenotype. Similar to humans, the levels of D90A protein were high. The levels of G127X hSOD1 were very low in the tissues but enriched in the CNS. Similarly, in an ALS patient heterozygous for G127X hSOD1, the levels of the mutant protein were overall very low, but highest in affected CNS areas. Despite the very different levels of mutant hSOD1, both D90A and G127X transgenic mice developed similar levels of detergent-resistant aggregates in the spinal cord when terminally ill. Surprisingly, mice overexpressing wild-type hSOD1 also developed detergent-resistant aggregates, although less and later. Most of the hSOD1 in the CNS of transgenic mice was inactive due to deficient copper charging or because of reduced affinity for the metal. The stabilizing intrasubunit disulfide bond of hSOD1 was partially or completely absent in the different hSOD1s. Both these alterations could increase the propensity of mutant hSOD1s to misfold and form aggregates.

The results presented here suggest that the motor neuron degeneration caused by mutant hSOD1s may be attributable to long-term exposure to misfolded, aggregation-prone, disulfide-reduced hSOD1s and that the capacity to degrade such hSOD1s is lower in susceptible CNS areas compared with other tissues. The data also suggest that wild-type hSOD1 has the potential to participate in the pathogenesis of sporadic ALS.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap, 2005. 119 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 981
Keyword
Neurosciences, aggregates, ALS, amyotrophic lateral sclerosis, cerebrospinal fluid, disulfide-reduced, inclusions, misfolded, protective factor, SOD1, transgenic, Neurovetenskap
National Category
Neurology
Research subject
Clinical Chemistry
Identifiers
urn:nbn:se:umu:diva-611 (URN)91-7305-936-6 (ISBN)
Public defence
2005-11-04, Sal B, 9 tr, 1D, Tandläkarhögskolan, 90185 NUS, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2005-10-13 Created: 2005-10-13 Last updated: 2009-11-18Bibliographically approved

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Bergemalm, DanielBrännström, ThomasNilsson, Peter

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