Scientists identify genes linked to brain cell loss in amyotrophic lateral sclerosis

In a small study, researchers discovered how a set of genes might cause neurons to die in cases of sporadic amyotrophic lateral sclerosis (ALS). The results, published in Natural agingprovide insight into the root causes of ALS and could lead to new ways to stop the progression of the disease.

ALS is a progressive neurological disorder that attacks motor neurons, the nerve cells in the brain and spinal cord that control muscles, leading to muscle weakness, paralysis and eventually death. Most cases of ALS are sporadic and occur in people without a family history or other obvious risk factors.

By analyzing the genetic profile of thousands of neurons from post-mortem brain tissue from people with ALS and healthy donors, researchers identified higher levels of risk genes for ALS and frontotemporal dementia (FTD). The genes were particularly important in Betz cells, a type of motor neuron, which express the marker THY1.

In people with ALS, this was linked to disruptions in other neurons, hindering their ability to build, transport and break down proteins. Genes including SOD1, KIF5A, and CCHHD10 are among the most commonly associated with ALS/FTD.

Additional experiments showed that these changes could be linked to toxic accumulation of the TDP-43 protein, a defining feature of ALS and some cases of FTD. Therefore, higher levels of ALS risk genes in a distinct cell type could trigger a detrimental chain reaction leading to widespread neuronal loss.

Betz cell degeneration is a hallmark of ALS and is thought to occur when symptoms first appear. Understanding what makes these and other cells vulnerable to ALS could lead to new treatments that slow or even stop the progression of the disease.

The team also explored how glial cells are affected by ALS. Glial cells are support cells that normally keep neurons healthy, but in ALS they can become dysfunctional and damage neurons, often hastening their death. Researchers analyzed genetic data from two types of glial cells and discovered genes linked to cellular stress and inflammation. Further research is needed to determine whether glial cell dysfunction is a consequence or cause of neuronal degeneration in ALS.

According to the researchers, the findings improve our understanding of why certain neurons are more susceptible to ALS and identify potential new therapeutic targets.