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Of mice and men: SOD1 associated human amyotrophic lateral sclerosis and transgenic mouse models
Umeå University, Faculty of Medicine, Medical Biosciences.
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 [en]
aggregates, ALS, amyotrophic lateral sclerosis, inclusions, misfolded, vacuolisation, SOD1, transgenic
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-1376ISBN: 978-91-7264-388-8 (print)OAI: oai:DiVA.org:umu-1376DiVA: diva2:140801
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
List of papers
1. Minute quantities of misfolded mutant superoxide dismutase-1 cause amyotrophic lateral sclerosis.
Open this publication in new window or tab >>Minute quantities of misfolded mutant superoxide dismutase-1 cause amyotrophic lateral sclerosis.
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2004 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, 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.

Keyword
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:nbn:se:umu:diva-15192 (URN)10.1093/brain/awh005 (DOI)14534160 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2017-12-14Bibliographically approved
2. Motor neuron disease in mice expressing the wild type-like D90A mutant superoxide dismutase-1.
Open this publication in new window or tab >>Motor neuron disease in mice expressing the wild type-like D90A mutant superoxide dismutase-1.
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2006 (English)In: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 65, no 12, 1126-1136 p.Article in journal (Refereed) Published
Keyword
Amyotrophic Lateral Sclerosis/*enzymology/*genetics/physiopathology, Animals, Disease Models; Animal, Disease Progression, Female, Humans, Inclusion Bodies/enzymology/genetics/pathology, Male, Mice, Mice; Inbred C57BL, Mice; Transgenic, Motor Neurons/enzymology/*pathology, Mutation/genetics, Nerve Degeneration/enzymology/genetics/physiopathology, Phenotype, Spinal Cord/enzymology/*pathology/*physiopathology, Superoxide Dismutase/*genetics/metabolism
Identifiers
urn:nbn:se:umu:diva-15273 (URN)17146286 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2017-12-14Bibliographically approved
3. SOD1-positive cytoplasmic and intranuclear inclusions are found in familial amyotrophic lateral sclerosis patients with the D90A superoxide dismutase 1 gene mutation
Open this publication in new window or tab >>SOD1-positive cytoplasmic and intranuclear inclusions are found in familial amyotrophic lateral sclerosis patients with the D90A superoxide dismutase 1 gene mutation
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Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-2593 (URN)
Available from: 2007-09-28 Created: 2007-09-28 Last updated: 2010-01-13Bibliographically approved
4. Widespread neuronal and astrocytic superoxide dismutase 1 inclusions in transgenic mouse models of ALS
Open this publication in new window or tab >>Widespread neuronal and astrocytic superoxide dismutase 1 inclusions in transgenic mouse models of ALS
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-2594 (URN)
Available from: 2007-09-28 Created: 2007-09-28 Last updated: 2010-01-13Bibliographically approved

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