Scientists ID gene activity changes linked to ALS neurodegeneration
Findings offer insights into potential new therapeutic targets for ALS
Researchers have identified gene activity changes that might explain why motor nerve cells selectively degenerate in amyotrophic lateral sclerosis (ALS), offering insights into the development of new therapeutic targets for the neurodegenerative disease.
In postmortem brain tissue, a particular group of these cells known to be lost in ALS showed greater activity of genes associated with ALS risk, which was accompanied by disruptions in normal protein dynamics. According to the National Institutes of Health (NIH), which funded the study and published a press release announcing its findings, “the researchers have discovered how a set of genes could cause neurons to die.”
The study, led by scientists from Harvard University in Massachusetts and titled “Single-nucleus sequencing reveals enriched expression of genetic risk factors in extratelencephalic neurons sensitive to degeneration in ALS,” was published in the journal Nature Aging.
“The results … provide insight into the root causes of ALS and may lead to new ways to halt disease progression,” the NIH stated in the release.
Study investigates links between gene activity and degeneration
ALS is characterized by the progressive loss of nerve cells, or motor neurons, involved in voluntary muscle control. A subgroup of motor neurons called Betz cells are especially vulnerable, but the reasons why are not known.
While there are genetic risk factors for the neurodegenerative disease, around 90% of cases are sporadic, or without a known cause. To learn more, the team of researchers sought to identify unique molecular properties of the cells that might make them especially sensitive to degeneration.
The researchers performed gene activity analyses from thousands of individual cells taken from postmortem brain tissue of five sporadic ALS patients and three people without ALS, who served as a control group. A wide range of different cell types were analyzed.
In both patients and controls, ALS-associated risk genes including SOD1, KIF5A, and CHCHD10 had elevated activity, or expression, specifically in Betz cells with THY1 gene activity.
For ALS patients, this was also linked to changes in other genes involved in regulating the normal balance of protein production, transport, and recycling — called proteostasis — as well as cellular stress responses in neurons.
In further lab experiments, the scientists confirmed that some of the observed genetic changes in ALS neurons are linked to disrupted protein dynamics, and specifically the toxic accumulation of the TDP-43 protein, which is observed in the vast majority of ALS patients.
The team also looked for genetic changes in glial cells, or nervous system support cells that keep neurons healthy in ALS patients.
They found that in oligodendrocytes — the glial cells responsible for producing the protective substance, called myelin, that surrounds nerve fibers — the activity of genes related to myelination was reduced. In microglia, the brain’s innate immune cells, there also was increased activity of genes associated with a pro-inflammatory state.
Findings provide ‘novel insights’ into cell involvement in ALS
Taken together, the researchers believe that increased activity of ALS-associated genes in the Betz cells leads to protein-related disruptions, including TDP-43 accumulation, that drives neurodegeneration. In turn, that leads to aberrant responses in glial cells that further exacerbate the damage.
“This view is a first insight into the disruptions of cortical biology in ALS and provides a connection between changes in cellular components and mechanisms associated with ALS,” the researchers wrote.
The scientists believe that future studies looking into therapeutic strategies should take into account the fact that perturbations are seen across multiple cell types.
While preserving motor neurons is “unmistakenly pivotal,” targeting other cell types to reduce inflammation or promote myelination may also be critical to “re-establish a neuroprotective environment,” they wrote.
This study provides novel insights [into] the involvement of different cell types in ALS and a different view [into] the motor cortex of patients with ALS.
Given the small number of patient samples, the researchers emphasized that future studies with a larger group of patients and more sophisticated analytical techniques “might further enrich the understanding of neurodegeneration in ALS.”
Nevertheless, the team notes their belief that “this study provides novel insights [into] the involvement of different cell types in ALS and a different view [into] the motor cortex of patients with ALS.”
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