The ALS (amyotrophic lateral sclerosis) Association revealed that a team of researchers funded by the Association and led by Dr. Timothy Miller and Dr. Randall Bateman from Washington University in Saint Louis, recently discovered important insights into the ALS-related protein called copper (Cu)/zinc (Zn) superoxide dismutase (SOD1).
ALS is a progressive neurodegenerative disease characterized by the gradual degeneration and atrophy of motor neurons in the brain and spinal cord that are responsible for controlling essential voluntary muscles, such as the ones related to movement, speaking, eating, and even breathing. ALS patients may become totally paralyzed and the majority die due to respiratory failure within two to five years post diagnosis. More than 300,000 Americans suffer from the disease and there is currently no cure or life-prolonging treatments.
It is estimated that around 10% of all ALS cases are inherited. The second most common cause of inherited forms of ALS occur due to mutations in the SOD1 gene, which encodes a key protein important for the detoxification of motor neurons. It is not clear how mutant SOD1 protein contributes to ALS development. Mutant SOD1 aggregates have been observed in patients, and it has been suggested that these have toxic properties. Arresting this aggregation process is therefore the goal of several therapeutic strategies. Recently, an approach called antisense therapy, where molecules that target the mutated SOD1 protein are employed, has been shown to reduce the amount of mutant protein in ALS patients.
In order to better understand SOD1 involvement in ALS and the effects of antisense therapy, it is important to know how quickly SOD1 protein can be degraded in the body. This is referred to as the protein’s half-life, meaning the time it takes for half of the protein to be degraded.
Researchers found that the normal SOD1 protein had a half-life of 16 days in rat cerebrospinal fluid and around 25 days in human cerebrospinal fluid, which was considered a relatively slow turnover rate in the nervous system. In terms of the mutant SOD1 protein, its half-life was found to be slightly faster in rats, while in humans it still needs to be determined in future studies.
The team believes that their findings can be important in the development of therapeutic trials evaluating strategies to reduce the levels of mutant SOD1 protein in patients. “This finding is a necessary step in the development of antisense therapy,” concluded the Chief Scientist for The ALS Association Dr. Lucie Bruijn in the news release. “These data will be used to help decide when and how often we will need to measure remaining mutant SOD1, in order to judge the effectiveness of antisense treatment. In that light, this study represents true progress toward a trial.”