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Overloading of stable and exclusion of unstable human superoxide dismutase-1 variants in mitochondria of murine amyotrophic lateral sclerosis models
Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi.
Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi.
Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
Umeå universitet, Medicinsk fakultet, Farmakologi och klinisk neurovetenskap, Neurologi.
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2006 (Engelska)Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 26, nr 16, s. 4147-4154Artikel i tidskrift (Refereegranskat) Published
Ort, förlag, år, upplaga, sidor
2006. Vol. 26, nr 16, s. 4147-4154
Nyckelord [en]
Amyotrophic Lateral Sclerosis/*enzymology/genetics, Animals, Disease Models; Animal, Enzyme Stability/genetics, Humans, Mice, Mice; Transgenic, Mitochondria/*enzymology/genetics, Mutation, Spinal Cord/enzymology, Superoxide Dismutase/*biosynthesis/genetics, Variation (Genetics)
Identifikatorer
URN: urn:nbn:se:umu:diva-15270DOI: 10.1523/JNEUROSCI.5461-05.2006PubMedID: 16624935OAI: oai:DiVA.org:umu-15270DiVA, id: diva2:154942
Tillgänglig från: 2008-01-11 Skapad: 2008-01-11 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Ingår i avhandling
1. Mutant superoxide dismutase-1-caused pathogenesis in amyotrophic lateral sclerosis
Öppna denna publikation i ny flik eller fönster >>Mutant superoxide dismutase-1-caused pathogenesis in amyotrophic lateral sclerosis
2010 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is a devastating disease that affects people in their late mid-life, with fatal outcome usually within a few years. The progressive degeneration of neurons responsible for muscle movement (motor neurons) throughout the central nervous system (CNS) leads to muscle wasting and paralysis, and eventually affects respiratory function. Most cases have no familial background (sporadic) whereas about 10% of cases have relatives affected by the disease. A substantial number of familial cases are caused by mutations in the gene encoding superoxide dismutase-1 (SOD1). Since the initial discovery of this relationship about 17 years ago, numerous workers have tried to identify the pathogenicity of mutant SOD1 but without any final agreement or consensus regarding mechanism. The experiments in this thesis have been aimed at finding common pathogenic mechanisms by analyzing transgenic mouse models expressing mutant SOD1s with widely different properties.

    Mitochondrial pathology and dysfunction have been reported in both ALS patients and murine models. We used density gradient ultracentrifugation for comparison of mitochondrial partitioning of SOD1 in our transgenic models. It was found that models with high levels of mutant protein, overloaded mitochondria with high levels of SOD1-protein whereas models with wild type-like levels of mutant protein did not. No significant association of the truncation mutant G127X with mitochondria was found. Thus, if mitochondrial dysfunction and pathology are fundamental for ALS pathogenesis this is unlikely to be caused by physical association of mutant SOD1 with mitochondria.

    Density gradient ultracentrifugation was used to study SOD1 inclusions in tissues from an ALS patient with a mutant SOD1 (G127X). We found large amounts in the ventral horns of the spinal cord but also in the liver and kidney, although at lower levels. This showed that such signs of the disease can also be found outside the CNS.

    This method was used further to characterize SOD1 inclusions with regard to the properties of mutant SOD1 and the presence of other proteins. The inclusions were found to be complex detergent-sensitive structures with mutant SOD1 reduced at disulfide C57-C146 being the major inclusion protein, constituting at least 50% of the protein content. Ten co-aggregating proteins were isolated, some of which were already known to be present in cellular inclusions. Of great interest was the presence of several proteins that normally reside in the endoplasmic reticulum (ER), which is in accordance with recent data suggesting that the unfolded protein response (UPR) has a role in ALS.

    To obtain unbiased information on the pathogenesis of mutant SOD1, we performed a total proteome study on spinal cords from ALS transgenic mice. By multivariate analysis of the 1,800 protein spots detected, 420 (23%) were found to significantly contribute to the difference between transgenic and control mice. From 53 proteins finally identified, we found pathways such as mitochondrial function, oxidative stress, and protein degradation to be affected by the disease. We also identified a previously uncharacterized covalent SOD1 dimer.

   In conclusion, the work described in this thesis suggests that mutant SOD1 affects the function of mitochondria, but not mainly through direct accumulation of SOD1 protein. It also suggests that SOD1 inclusions, present in both the CNS and peripheral tissues, mainly consist of SOD1 but they also trap proteins involved in the UPR. This might be deleterious as motor neurons, unable to renew themselves, are dependent on proper protein folding and degradation.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå university, 2010. s. 89
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1285
Nyckelord
ALS, SOD1, mitochondria, proteome, transgenic mice, inclusion
Nationell ämneskategori
Annan klinisk medicin
Forskningsämne
biokemi; neurologi; klinisk kemi; patologi
Identifikatorer
urn:nbn:se:umu:diva-31116 (URN)978-91-7264-838-8 (ISBN)
Disputation
2010-02-26, Betula, NUS, 90185, Umeå, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2010-02-05 Skapad: 2010-01-29 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

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