SOD1 gene mutations can contribute differently to the degenerative process of nerve cells involved in the progression of amyotrophic lateral sclerosis (ALS), newly developed worm models of the disease reveal.
This finding was reported in the study, “Single copy/knock-in models of ALS SOD1 in C. elegans suggest loss and gain of function have different contributions to cholinergic and glutamatergic neurodegeneration,” which appeared in the journal PLOS Genetics.
Defective SOD1 protein can cause overproduction of potentially damaging reactive compounds, also known as ROS, promoting cellular oxidative stress. In addition, it leads to the accumulation of the encoded protein, which becomes toxic to nerve cells, causing their death.
Analysis of ALS patients’ nerve cells has revealed that faulty SOD1 can induce different manifestations of the disease, including variable age of onset, progression, severity, and duration, depending on the genetic mutation.
SOD1 variants have been found to inevitably lead to degeneration of cholinergic motor nerve cells (spinal neurons), a hallmark of ALS. It can also affect survival of glutamate-producing nerve cells in the brain; however, this feature is not present in all SOD1-affected ALS patients.
“How mutant SOD1 mediates its toxic function in different neuronal populations remains largely unknown,” researchers said.
To better understand the underlying mechanisms induced by SOD1 mutations in motor nerve cell subsets, Brown University researchers developed new worm models of the disease.
Taking advantage of the CRISPR/Cas9 genome editing method, the team introduced mutations previously reported in ALS patients to the SOD1 genetic sequence of worms.
With this strategy, they found that mutations that led to loss of function of SOD1 did not induce the formation of protein aggregates in motor neurons. Still, most of the tested variants that induced gain of function did induce the accumulation of misfolded proteins as previously reported.
Although the presence of SOD1 variants alone did not have a major impact on motor cells’ survival, when exposed to high levels of oxidative stress they dramatically decreased survival and showed increased accumulation of protein aggregates.
Further analysis revealed that the impact of the SOD1 variants differed significantly among different types of nerve cells.
While in the presence of gain-of-function mutations, oxidative stress led to loss of cholinergic motor neurons. But the loss of SOD1 did not induce neurodegeneration of this population of cells under high oxidative stress levels.
Other cell populations such as dopamine, serotonin, and GABA-producing nerve cells, which can also regulate muscle activity through the central nervous system, were found to be spared from SOD1 variants’ damaging effects. In contrast, the tested gain- and loss-of-function mutations were found to lead to a 20-30% reduction in the number of glutamate-producing nerve cells.
Supported by these findings, the researchers suggest that “an underlying premise of the ALS field —that identical [disease-trigger] mechanisms lead to degeneration of cholinergic and glutamatergic neurons — should perhaps be reconsidered.”
“Our results raise the possibility that the glutamatergic neurons in the brains of some ALS patients die in ways that are somehow different than how the spinal cord neurons die,” Anne Hart, a professor at Brown and senior author of the study, said in a university news release.
Additional studies are warranted to confirm that SOD1-driven mechanisms described in this worm study also occur in the human disease and can help explain the neurodegenerative process in ALS.
“We can now use these new ALS models to find other proteins and genes that we can use to stop neurodegeneration in worms,” said Hart, who is also a researcher at Carney Institute for Brain Science.
She and her team are planning to use these newly developed worm models to test small molecules as potential therapeutic agents for ALS, and to find other genes involved in the neurodegenerative process.
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