Study: SOD1 Protein could have Therapeutic Implications Beyond Familial ALS


In a study published in the neuroscience journal Brain, researchers found that the link between the Superoxide dismutase 1 (SOD1) protein and Amyotrophic Lateral Sclerosis (ALS) could extend to all types of the motor neuron disease.

The study, highlighted Saturday in Neuroscience News, found there is an accumulation of the mutated protein in the spinal cords of patients who had died from ALS.

Previous research had shown that there were accumulations of this protein in animal models of ALS, but the research team from the University of Sydney’s Brain and Mind Center has found the first evidence of this phenomenon in post-mortem human tissue samples.

"We have shown for the first time that mechanisms of disease long hypothesized to occur in animal and cellular models are present in patients with motor neuron disease," Dr. Benjamin Trist, the study’s lead author, told Neuroscience News. “This is a significant milestone in our understanding of ALS and motor neuron disease more broadly.”

ALS is a progressive, neurodegenerative disease that affects the spinal cord and brain tissue. Patients typically succumb to the disease within 2 to 5 years from the time of diagnosis. While there are two disease-modifying treatments for ALS, Riluzole, approved by the FDA in 1995, and Mitsubishi Tanabe’s Radicava (edaravone), a cure remains elusive.

A mutation in the SOD1 gene is believed to be the genetic driver in SOD1-ALS, the second most common form of inherited ALS. Typically, this protein protects cells from oxidative stress, but in ALS patients, there is a mutation on the gene which gives it a near toxic effect. It is thought to impact the cell through the cell death cycle, as it is only found in the spinal cord in clusters where this has occurred.

Notably, the researchers found mislocalization and accumulation of structurally-disordered, immature SOD1 protein conformers in sporadic cases of ALS and non-SOD1-linked familial ALS cases. This could mean the SOD1 protein is an essential factor across all types of ALS.

“The results suggest this abnormal protein contributes to cell death in many forms of neuron disease, not just rare genetic cases of motor neuron disease,” Professor Kay Double, senior study author, told Neuroscience News. “It’s a big step in advancing our understanding of motor neuron disease. Our findings will direct further research and could ultimately lead to more effective treatments,” she added.

Last month, the U.S. FDA accepted Biogen and Ionis’ New Drug Application for tofersen, which is being developed as a potential treatment for SOD1-ALS. While tofersen failed to meet the primary endpoint of improvements in disease activity from baseline, as measured by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), efficacy signals were seen across secondary and exploratory endpoints.

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