Researchers from the University of North Carolina School of Medicine have solved the structure of a toxic protein aggregate that causes Amiotrophic Lateral Sclerosis (ALS). Mutants of the Cu,Zn superoxide dismutase (SOD1) protein prone to form trimers aggregated and increased neuron death. This is the first experimental evidence of protein aggregates causing the neurodegenerative disease. The study was published in the Proceedings of the National Academy of Society.
ALS patients suffer loss of motor neurons, which leads to muscle paralysis. They progressively lose the ability to move, eat, speak or breath. On average, patients die after three years of onset. Most neurodegenerative diseases are characterized by the presence of protein aggregates in neurons, which are thought to cause neuron death. However, the molecular mechanism linking protein aggregation to cell death is unclear. For example, SOD1 mutations have been linked to ALS for more than 20 years, but scientists have not found how they cause motor neuron death. SOD1 protein folding and stability have been fully characterized, but it is yet unknown which folding intermediate is the cytotoxic species.
SOD1 structure solved by experimental data and simulations
In their last paper, Nikolay Dokholyan and his team present evidence of the SOD1 cytotoxic aggregates for the first time: a nonnative protein trimer. They solved SOD1 structure by combining experimental data and simulations to model metastable aggregation intermediates. Dokholyan’s team discovered that neuron death was caused by SOD1 mutats prone to form trimers. They later demonstrated that cell death correlates with the trimer stability, determining that oligomer misfolding is directly linked to motor neuron death and ALS. When aggregates are unstable, they interact with parts of the cell they normally don’t, contributing to cell death.
Knowing the cytotoxic species responsible for aggregate formation and neuron death is key to design therapies against ALS. Therapeutic strategies will be directed to avoid the formation of the trimeric species of SOD1.