Change search
ReferencesLink to record
Permanent link

Direct link
Identification of property outliers among ALS-associated SOD1 mutations: Common effect on surface hydrogen bonds
Umeå University, Faculty of Science and Technology, Chemistry.
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
Umeå University, Faculty of Science and Technology, Chemistry.
Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden.
(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
Abstract [en]

In good accord with the protein-aggregation hypothesis for neurodegenerative diseaseALS-associated SOD1 mutations are found to reduce structural stability or netrepulsive charge. Moreover there are weak indications that the ALS diseaseprogression is correlated with the degree of mutational impact on the SOD1 structure.A bottleneck for obtaining more conclusive information about these structure-diseaserelationships, however, is the large intrinsic variability in patient survival times andinsufficient disease statistics for the majority of ALS-provoking mutations. As analternative test of the structure-disease relationship we focus here on the SOD1 amutation that appears to be outliers in the data set. The results identify several ALSprovokingmutations whose only effect on apo SOD1 is the elimination orintroduction of a single charge, i.e., D76V/Y, D101N and N139D/K. Thethermodynamic stability and folding behaviour of these mutants are indistinguishablefrom the wildtype control, showing that structurally benign replacements of individualsurface charges are sufficient to trigger ALS. Moreover, D101N is a clear outlier inthe plot of stability loss vs. patient survival time by having too rapid diseaseprogression. Common to the identified mutations is that they truncate conserved saltlinksand/or H-bond networks in the functional loops IV or VII. The results show thatthe local impact of ALS-associated mutations on the SOD1 molecule can sometimesoverrun their global effects on stability and net repulsive charge, and point at theanalysis of property outliers as an efficient strategy for mapping out new ALSprovokingfeatures.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
URN: urn:nbn:se:umu:diva-26315OAI: diva2:241784
Available from: 2009-10-05 Created: 2009-10-05 Last updated: 2010-01-14
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

Open Access in DiVA

No full text

Search in DiVA

By author/editor
Byström, RoberthAndersen, Peter MunchGröbner, Gerhard
By organisation
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Total: 54 hits
ReferencesLink to record
Permanent link

Direct link