Principal Investigators

    Peter Andersen


    Umeå University

    Contact information of lead PI



    Title of project or programme

    ALS as a Model System for Studying Degenerative Brain Diseases

    Source of funding information

    The Wallenberg Foundations

    Total sum awarded (Euro)

    € 3,895,538

    Start date of award


    Total duration of award in years


    The project/programme is most relevant to:

    Motor neurone diseases


    Research Abstract

    The common denominator for all fatal neurodegenerative diseases is the formation of protein aggregations in affected neurons. The role of these aggregations remains elusive due to the intrinsic difficulty of studying the molecular behavior of proteins inside living cells. We here present a plan for overcoming this problem. Our model system is amyotrophic lateral sclerosis (ALS), associated with misfolding and aggregation of the ubiquitous enzyme superoxide dismutase-1 (SOD1). Using a novel epitope-mapping approach, we recently observed in transgenic ALS model mice that SOD1 aggregates are of two types with distinct molecular structures: type A and type B. The key feature of type A and type B aggregates is that they are associated with different severities of disease progression. These in vivo aggregates are different to those produced in earlier in vitro models. Analysis of different to those produced in earlier in vitro models. Analysis of aggregate patterns in different parts of the CNS suggests a local initiating event which subsequently spreads. The structural polymorphism shows that living cells not only control how SOD1 aggregates, but that the outcome of this control can vary with direct effect on ALS pathogenesis and prognosis. This new link between aggregate structure and in vivo pathology presents a unique handle on the role of protein deposition in disease. Of importance is to identify which aggregate properties modulate the toxic response. Is it their ability to destabilize cellular components, their propensity to spread new seeds, and/or simply their resistance to cellular turn-over? To find out, we will use a combination of aggregate structure mapping in vivo, CNS seeding and mouse strain crossing experiments, and atomic-resolution analysis of SOD1 misfolding and aggregation inside living neurons by NMR. Our multidisciplinary approach targets the missing gap between neural damage and high-resolution protein structure, which is the key obstacle for the development of effective treatments for degenerative diseases.

    Lay Summary

    Further information available at:

Types: Investments > €500k
Member States: Sweden
Diseases: Motor neurone diseases
Years: 2016
Database Categories: N/A
Database Tags: N/A

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