Insight into the Role of SOD1 in the Proteopathy of ALS

Researchers here uncover more details of the role of SOD1 in killing cells in amyotrophic lateral sclerosis (ALS). Many degenerative conditions are associated with proteopathy, cell damage and death caused by the abnormal clumping or misfolding of specific proteins. The caveat with this research, as for many similar lines of work, is that it results from investigations of individuals with a mutation that predisposes them to suffer the disease. The mechanisms outlined here may or may not also be central and important to the development of ALS in genetically normal individuals, but given what is known to date it seems promising.

Patients with ALS suffer gradual paralysis and early death as a result of the loss of motor neurons, which are crucial to moving, speaking, swallowing, and breathing. The study focuses on a subset of ALS cases - an estimated 1 to 2 percent - that are associated with variations in a protein known as SOD1. However, even in patients without mutations in their SOD1 gene, this protein has been shown to form potentially toxic clumps. The researchers discovered that the protein forms temporary clumps of three, known as a "trimer," and that these clumps are capable of killing motor neuron-like cells grown in the laboratory. "This is a major step because nobody has known exactly what toxic interactions are behind the death of motor neurons in patients with ALS. Knowing what these trimers look like, we can try to design drugs that would stop them from forming, or sequester them before they can do damage. We are very excited about the possibilities."

Researchers zeroed in on SOD1 after genetic mutations affecting the protein were linked with ALS in the early 1990s. But the exact form of aggregated protein that is responsible for killing neurons has been hard to identify, and many of the clumps that are thought to be toxic disintegrate almost as soon as they form, making them exceedingly difficult to study. "It is thought that part of what makes them so toxic is their instability. Their unstable nature makes them more reactive with parts of the cell that they should not be affecting." Until now, researchers did not know what these fleeting clumps looked like or how they might affect cells.

To crack the mystery, the research team used a combination of computational modeling and experiments in live cells. Researchers spent two years developing a custom algorithm to determine the trimers' structure, an aspect of the study akin to mapping the structure of a ball of yarn after taking snippets of just its outermost layer and then figuring out how they fit together. Once the trimers' structure was established, the team spent several more years developing methods to test the trimers' effects on motor neuron-like cells grown in the laboratory. The results were clear: SOD1 proteins that were tightly bound into trimers were lethal to the motor neuron-like cells, while non-clumped SOD1 proteins were not. The team plans to further investigate the "glue" that holds the trimers together in order to find drugs that could break them apart or keep them from forming.

Link: http://news.unchealthcare.org/news/2015/december/new-study-opens-new-door-for-als-drug-discovery

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