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Systematically perturbed folding patterns of amyotrophic lateral sclerosis (ALS)-associated SOD1 mutants
Umeå University, Faculty of Science and Technology, Chemistry.
Umeå University, Faculty of Science and Technology, Chemistry.
Umeå University, Faculty of Science and Technology, Chemistry.
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
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2005 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, Vol. 102, no 28, 9754-9 p.Article in journal (Refereed) Published
Abstract [en]

Amyotrophic lateral sclerosis is a neurodegenerative syndrome associated with 114 mutations in the gene encoding the cytosolic homodimeric enzyme Cu/Zn superoxide dismutase (SOD). In this article, we report that amyotrophic lateral sclerosis-associated SOD mutations with distinctly different disease progression can be rationalized in terms of their folding patterns. The mutations are found to perturb the protein in multiple ways; they destabilize the precursor monomers (class 1), weaken the dimer interface (class 2), or both at the same time (class 1 + 2). A shared feature of the mutational perturbations is a shift of the folding equilibrium toward poorly structured SOD monomers. We observed a link, coupled to the altered folding patterns, between protein stability, net charge, and survival time for the patients carrying the mutations.

Place, publisher, year, edition, pages
National Academy of Sciences , 2005. Vol. 102, no 28, 9754-9 p.
Keyword [en]
neurodegenerative disease, protein stability
URN: urn:nbn:se:umu:diva-14675DOI: 10.1073/pnas.0501957102OAI: diva2:154347
Available from: 2007-11-22 Created: 2007-11-22 Last updated: 2009-10-07Bibliographically approved
In thesis
1. SOD1´s Law: An Investigation of ALS Provoking Properties in SOD1
Open this publication in new window or tab >>SOD1´s Law: An Investigation of ALS Provoking Properties in SOD1
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Proteins are the most important molecules in the cell since they take care of most of the biological functions which resemble life. To ensure that everything is working properly the cell has a rigorous control system to monitor the proper function of its proteins and sends old or dysfunctional proteins for degradation. Unfortunately, this system sometimes fails and the once so vital proteins start to misbehave or to accumulate and in the worst case scenario these undesired processes cause the death of their host. One example is Amyotrophic Lateral Sclerosis (ALS); a progressive and always fatal neurodegenerative disorder that is proposed to derive from accumulation of aberrant proteins. Over 140 mutations in the human gene encoding the cytosolic homodimeric enzyme Cu/Zn-Superoxide Dismutase (SOD1) are linked to ALS. The key event in SOD1 associated ALS seems to be the pathological formation of toxic protein aggregates as a result of initially unfolded or partly structured SOD1-mutants.

Here, we have compared the folding behaviour of a set of ALS associated SOD1 mutants. Based on our findings we propose that SOD1 mediated ALS can be triggered by a decrease in protein stability but also by mutations which reduce the net charge of the protein. Both findings are in good agreement with the hypothesis for protein aggregation.

SOD1 has also been found to be able to interact with mitochondrial membranes and SOD1 inclusions have been detected in the inter-membrane space of mitochondria originating from the spinal cord. The obvious question then arose; does the misfolding and aggregation of SOD1 involve erroneous interactions with membranes?

Here, we could show that there is an electrostatically driven interaction between the reduced apo SOD1 protein including ALS associated SOD1-mutants and charged lipid membrane surfaces. This association process changes the secondary structures of these mutants in a way quite different from the situation found in membrane free aqueous environment. However, the result show that mutants interact with charged lipid vesicles to lesser extent than wildtype SOD1. This opposes the correlation between decreased SOD1 stability and disease progression. We therefore suggest that the observed interaction is not a primary cause in the ALS mechanism.

Place, publisher, year, edition, pages
Umeå: Kemiska instsitutionen, Umeå universitet, 2009. 65 p.
ALS, amyotrophic lateral sclerosis, SOD1, protein folding, membrane interaction, aggregates, survival time, repulsive charge
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
urn:nbn:se:umu:diva-26319 (URN)978-91-7264-856-2 (ISBN)
Kemi, 90187, Umeå
Public defence
2009-10-30, KB3B1, Umeå universitet, KBC, Linnaeus väg 6, Umeå, 10:00 (English)
Available from: 2009-10-09 Created: 2009-10-05 Last updated: 2009-10-09Bibliographically approved

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