By studying SOD1 in mice genetically engineered with a form of ALS, UF doctoral student Celeste Karch demonstrated that the protein clumps appear in spinal cord tissues later in the disease, about the same time that symptoms appear, but well after cell damage occurs from nerve loss and the formation of fluid-filled pockets called vacuoles.

The finding suggests the aggregated proteins may elude normal cellular "housecleaning" methods, or their formation is heightened by stress conditions in the cell.

"As the disease enters the symptomatic stage in mice, the buildup of protein is rapid and dramatic," Borchelt said. "However, the formation of these aggregates is not the whole story. It is well established that significant damage to the nervous system occurs well before the symptoms appear. The uncontrolled misfolding of SOD1 seems to be confined to the late stage of disease, which is when symptoms first appear, giving hope that treatments targeting this process could be beneficial."

Furthermore, the findings suggest that there is a larger therapeutic window to treat ALS, if scientists can find a way to diagnose the disease before the hallmark protein clumping begins.

"Many scientists had accepted that protein aggregation was tied to the causation of ALS," said Joan Selverstone Valentine, Ph.D., a UCLA professor of chemistry and biochemistry who did not participate in the study. "But this research shows these aggregates form during disease progression, not initiation. It is important to know what to look for as an early cause of the disease and what causes it to get more severe. That means we have to look for something upstream of aggregation as a cause, as well as understand the steps in the progress. If you can prevent or halt the aggregation, you can stop the disease in its tracks. That's as good as a cure if it can be done early enough."

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