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SOD1

SOD1
The effects of ALS-linked mutations upon the stability of species populated during the folding reaction and how they could result in pathological aggregation is shown on a reaction coordinate diagram with the crystal structure of our dimeric SOD1 model shown for reference.

Superoxide dismutase (SOD1) is a ubiquitously expressed homodimeric protein whose monomers are comprised of 8 b-strands forming a clam-like structure in its native, functional conformation. Mutations at dozens of positions in the sequence of SOD1 have been linked to the fatal neurodegenerative disease, amyotrophic lateral sclerosis (ALS). ALS is caused by the progressive death of motor neurons, and a hallmark of the disease is the presence of large intracellular aggregates comprised mainly of mutant SOD1. When mapped to the sequence of SOD1, the ALS-linked variants are distributed throughout the protein (Figure X1). The most parsimonious conclusion is that all share a common gain of function toxicity, i.e., aggregation, leading to ALS. Biophysical analysis with a spectrum of technologies are used to map the perturbations in the folding free energy landscapes of mutant SOD1 that favor aggregation over folding (Figure X2). Current attention is focused on the long-lived unfolded state as the source of nucleation that drives aggregation and leads to disease.