Synchrotron X-ray studies on the stability of dimeric native and fALS mutant structures of CuZnSOD1: Structure based lead optimisation with the aim of stabilising the structure

Description:

What this research means to you: Some cases of the rare inherited form of MND are caused by abnormal changes in a protein known as SOD1. Normally present in cells as two protein molecules stuck together, SOD1 falls apart when damaged. Building on their earlier work, these researchers will now examine potential drugs to see how well they “mend” abnormal SOD1 molecules and how they can be made even more effective.

The researchers explain in detail: “ALS is the most common form of motor neurone disease and involves both upper motor neurones (those running from the brain to the spinal cord) and lower motor neurones (those running from the spinal cord out to the muscles). About 10% of all ALS cases are familial (FALS), meaning that they are caused by inherited genetic damage known as mutations. Inheritance of damage to the enzyme CuZn superoxide dismutase (SOD1) is involved in about 20% of FALS. This well characterised sub-set of FALS offers the best chance of understanding the origin of the disease and arriving at a general strategy for a cure. Current research strongly suggests a gain of a toxic property in this otherwise key life-sustaining enzyme.
Our work, funded by the MND Association, has provided evidence that (1) mutations impair the stability of SOD1 molecules so that they fall apart, and (2) that the pieces of the molecule then clump together or stick to other molecules in the neurone, creating obstructions to normal processes. These factors are the most probable reasons for SOD1 toxicity and for disease progression. We are in a unique position for identifying potential ‘drug binding pockets’ on SOD1 using the mutant SOD1 structures we have already determined, and to search for compounds with that may help stabilise SOD1 and stop it from falling apart. We will examine potential drugs identified so far, as well as new compounds, to investigate how effective they are at attaching to the SOD1 molecule. Once binding sites for these potential drugs on SOD1 mutants have been identified, we will collaborate with another researcher to test the drugs for their ability to correct the disease-causing behaviour of SOD1. Our structural studies will also allow us to make improvements to potential drugs so that they are better able to bind to SOD1.”