Loss of protein in ALS silences key nerve cell communication gene
Findings from lab study point to new avenue for treatment: Researchers
In amyotrophic lateral sclerosis (ALS), the loss of any one of four RNA-binding proteins turns off a gene called UNC13A that needs to stay active for nerve cells to communicate with each other — with three of them leading to an excess of another protein, REST — pointing to a new avenue for treatment.
That’s according to a new study by researchers in Japan, the findings of which highlight the key role of UNC13A in ALS development, per the team.
“This study provides a valuable framework for developing broad-spectrum treatments that target shared molecular vulnerabilities in ALS,” Keiko Nakayama, PhD, a professor at Tohoku University and the study’s senior author, said in a university press release.
Conducted in lab-grown cells, the work was detailed in “ALS-associated RNA-binding proteins promote UNC13A transcription through REST downregulation,” a study published in The EMBO Journal.
The researchers say the study’s findings provide a basis for the development of new treatments that target REST and its activity.
ALS occurs when motor neurons — the nerve cells that control voluntary movement — become damaged, leading to muscle weakness. As a result, people with the neurodegenerative disease experience progressive difficulties in performing everyday tasks, such as walking, speaking, and breathing.
While the causes of ALS remain unclear, genetics have been shown to play a key role. Yet, according to Yasuaki Watanabe, MD, PhD, the study’s first author, “scientists still don’t fully understand the process behind the loss of motor neurons in ALS.”
Indeed, Watanabe noted that “ALS is known for its genetic heterogeneity — meaning that there are numerous possible combinations of genes and factors that could lead” to the disease’s development.
“This makes it difficult to develop a singular treatment that works for everyone,” Watanabe said.
Nerve cell communication in ALS tied to UNC13A gene
A hallmark of ALS is the buildup of toxic clumps of TDP-43, a protein that helps control the activity of genes by binding to RNA, the molecule that carries genetic instructions from a cell’s nucleus to produce proteins. In ALS, TDP-43 moves out of the cell’s nucleus and loses its function, damaging motor neurons in both familial and sporadic forms of the disease.
Among other genes, TDP-43 controls UNC13A, which encodes a protein that aids in nerve cell communication. It works to prepare synaptic vesicles — small sacs that carry chemical messages — for release at the points where nerve cells connect. Three other RNA-binding proteins linked to ALS, namely MATR3, FUS, and hnRNPA1, also help control how active UNC13A is.
Here, the team used in their work lab-grown nerve cells missing any one of the four RNA-binding proteins. The researchers identified a group of genes important for nerve cell communication that were commonly turned off — especially UNC13A. These modified nerve cells all had abnormal shapes and showed signs of stress, suggesting that loss of UNC13A affects how they function.
Without TDP-43, UNC13A is copied from DNA to RNA but becomes unstable due to cryptic exons — faulty segments that are normally removed — causing the RNA to break down. In nerve cells lacking MATR3, FUS, or hnRNPA1, UNC13A is reduced not because it’s destroyed, but because its production is disrupted, the research showed.
Researchers find REST protein can turn off UNC13A gene
Indeed, the team found that instead of acting directly on UNC13A like TDP-43 does, the three other RNA-binding proteins control another protein called REST, which can turn off the UNC13A gene. The presence of MATR3, FUS, and hnRNPA1 would reduce the amount of REST in nerve cells, allowing UNC13A to stay active.
When any of these three RNA-binding proteins are missing, the amount of REST increases. REST then attaches to the beginning of the UNC13A gene and turns it off. This means nerve cells will not produce enough protein, which may lead to damage and loss of function.
The identification of this mechanism may provide a basis for the development of new therapeutic agents for ALS that target REST [protein] activity.
Similar observations were made in nerve cells and tissue samples from patients diagnosed with ALS with familial or sporadic ALS. Understanding this mechanism — from loss of RNA-binding proteins to increased REST and reduced activity of the UNC13A gene — offers a clearer picture of what may cause ALS to develop, the researchers noted.
“The identification of this mechanism may provide a basis for the development of new therapeutic agents for ALS that target REST activity,” the team wrote, suggesting that keeping REST under control may help protect nerve cells, potentially slowing the progression of the disease.
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