In amyotrophic lateral sclerosis (ALS), the motor nerve cells that control the body's muscles die. The most common cause is inherited mutations in the protein superoxide dismutase-1 (SOD1), which is found in 6% of cases. We have recently presented evidence that normal SOD1 is also involved in the majority of ALS cases that lack mutations. The project aims to investigate this link further to understand the factors that trigger the disease. The studies are based, among other things, on transgenic mice that develop ALS during production of human SOD1 in the spinal cord. Complementary studies are focused on ALS patients without SOD1 mutations, and on patients with the related disease frontal lobe dementia. A second goal is to clarify how SOD1 causes ALS at the molecular level. Aggregation of SOD1 in neurons is central to the disease. We see that SOD1 aggregates are of two different types, depending on the mutation, and that ALS pathology differs between these aggregates. This link between aggregate type and pathology is found in the infectious prion diseases. We will now investigate whether the SOD1 aggregates can spread the disease via injection in the nervous system of transgenic mice with varying genetic backgrounds. Furthermore, we will map at the atomic level how the aggregates arise inside living human cells with newly developed strategies based on NMR. The goal is to identify suitable targets in SOD1 for targeted therapy with antibodies, which, by inhibiting aggregation, slow or prevent the spread of the disease in the nervous system.