The researchers identified changes in gene activity that could explain why motor neurons selectively degenerate. Amyotrophic lateral sclerosis This will provide insights that will lead to the development of new therapeutic targets for the neurodegenerative disease amyotrophic lateral sclerosis (ALS).
In postmortem brain tissue, specific groups of these cells, known to be lost in ALS, showed increased activity of genes associated with ALS risk, along with disruptions to normal protein dynamics, according to the National Institutes of Health (NIH), which funded and published the study. press release Announcing their findings, the researchers said: “The researchers have discovered how a series of genes triggers the death of neurons.”
Led by scientists from Harvard University in Massachusetts,Single-nucleus sequencing reveals enriched expression of genetic risk factors in extracerebral neurons susceptible to ALS degeneration” was published in the journal Natural aging.
“These findings provide insight into the underlying causes of ALS and may lead to new ways to halt disease progression,” the NIH said in a statement.
Studies investigating the relationship between gene activity and degeneration
ALS is characterized by the gradual loss of nerve cells, or motor neurons, involved in controlling voluntary muscles. A subgroup of motor neurons called Betz cells is particularly susceptible, for reasons that are unclear.
genetically Risk factor In neurodegenerative diseases, approximately 90% of cases Sporadicor the cause is unknown. To learn more, the team sought to identify unique molecular properties of the cells that might make them particularly susceptible to degeneration.
The researchers performed gene activity analysis on thousands of individual cells from postmortem brain tissue of five people with sporadic ALS and three control individuals without ALS.
In both patients and controls, ALS-associated risk genes include: SOD1, KIF5A, and $ 10 The activity or expression was particularly increased in Betz cells. THY1 Gene activity.
In ALS patients, this was also associated with 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 experiments, the scientists confirmed that some of the genetic changes they observed in ALS neurons are linked to disturbances in protein dynamics, in particular the toxic accumulation of the TDP-43 protein, which is found in the majority of ALS patients.
The team also looked for genetic changes in glial cells, the nervous system support cells that keep neurons healthy in ALS patients.
The researchers found decreased activity of genes related to myelination in oligodendrocytes (glial cells responsible for producing the protective substance called myelin that surrounds nerve fibers), and increased activity of genes associated with a pro-inflammatory state in microglial cells, the brain’s innate immune cells.
Study results provide “new insights” into cellular involvement in ALS
Taken together, the researchers believe that increased activity of ALS-related genes in Betz cells drives neurodegeneration by triggering protein-related disruptions, including the accumulation of TDP-43, which in turn triggers an abnormal response in glial cells, further exacerbating the damage.
“This finding provides the first insight into the disruption of cortical biology in ALS and provides a link between altered cellular components and ALS-relevant mechanisms,” the researchers write.
The scientists believe that future studies looking at treatment strategies should take into account the fact that variation is seen across multiple cell types.
Although preserving motor neurons is “undoubtedly crucial,” targeting other cell types to reduce inflammation or promote myelination may also be important to “re-create a neuroprotective environment,” the researchers wrote.
This study provides new insights [into] Different cell types involved and different perspectives on ALS [into] Motor cortex in ALS patients.
The researchers emphasized that given the small patient sample size, future studies using larger patient groups and more sophisticated analytical techniques “may lead to a greater understanding of neurodegeneration in ALS.”
Still, the team said they believe “this study provides new insights.” [into] Different cell types involved and different perspectives on ALS [into] “The motor cortex of ALS patients”
