Mapping the genetic mutations in the SOD1 protein that cause ALS to improve its early diagnosis and treatment.

Benedetta Bolognesi

Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain

Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease. Each year, about two cases are diagnosed per 100,000 inhabitants. It is characterised by the progressive degeneration of nerve cells in the spinal cord and brain, leading to the loss of muscular and respiratory capacity. Currently, the life expectancy of patients after diagnosis is about five years.

Genetic studies have identified a number of mutations that cause familial (hereditary) forms of the disease. For example, more than 180 mutations associated with ALS have been found in the SOD1 protein so far. Patients with these mutations have been found to have extremely variable survival rates.

It is not fully understood how each of the mutations contributes to causing the disease, which hampers the development of new treatments. In addition, each year new alterations in this gene are discovered whose involvement in the disease is still unknown, which contributes to making diagnosis and the administration of appropriate drugs a slow process for patients.

In this regard, the current project will analyse all possible alterations in the SOD1 protein that may lead to the development of the disease. To achieve this, on the one hand, a map will be created to indicate how each of these mutations affects the protein, aiming to understand the different mechanisms that cause the disease; this could pave the way for the development of new drugs to treat it. On the other hand, such a map will also allow accurate prediction of whether a specific mutation in the SOD1 protein will cause ALS, which will facilitate earlier and more accurate diagnosis of the disease.

• Bryony Thompson, The Royal Melbourne Hospital, Australia

• Luke McAlary, University of Wollongong, Australia

Deep mutational scanning of SOD1 to map mechanisms of toxicity and test novel therapeutics

€981,070.19

*Award-winning project, in collaboration with the Fundación Francisco Luzón