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Motor neuron disease in mice expressing the wild type-like D90A mutant superoxide dismutase-1.
Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi. Klinisk kemi.
Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi. Patologi.
Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi. Patologi.
Vise andre og tillknytning
2006 (engelsk)Inngår i: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 65, nr 12, s. 1126-1136Artikkel i tidsskrift (Fagfellevurdert) Published
sted, utgiver, år, opplag, sider
2006. Vol. 65, nr 12, s. 1126-1136
Emneord [en]
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
Identifikatorer
URN: urn:nbn:se:umu:diva-15273PubMedID: 17146286OAI: oai:DiVA.org:umu-15273DiVA, id: diva2:154945
Tilgjengelig fra: 2008-01-11 Laget: 2008-01-11 Sist oppdatert: 2018-06-09bibliografisk kontrollert
Inngår i avhandling
1. Of mice and men: SOD1 associated human amyotrophic lateral sclerosis and transgenic mouse models
Åpne denne publikasjonen i ny fane eller vindu >>Of mice and men: SOD1 associated human amyotrophic lateral sclerosis and transgenic mouse models
2007 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Umeå: Medicinsk biovetenskap, 2007. s. 74
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1118
Emneord
aggregates, ALS, amyotrophic lateral sclerosis, inclusions, misfolded, vacuolisation, SOD1, transgenic
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-1376 (URN)978-91-7264-388-8 (ISBN)
Disputas
2007-10-19, sal C, 9 tr, 1D, Tandläkarhögskolan, Umeå, 13:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2007-09-28 Laget: 2007-09-28 Sist oppdatert: 2018-01-13bibliografisk kontrollert

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