New tests identify a critical gene for treatment

Amyotrophic lateral sclerosis (ALS) – which you can know as a disease that affected Stephen Hawking – is a deadly neurodegenerative disease that causes progressive muscle weakness. The research team at the University of Tohoku and the University of Keio has discovered a mechanism of uniting in ALS turning around UNC13A expression (key gene for neuronal communication), which is a common goal to develop effective treatment strategies that could improve the lives of patients from ALS.

“Scientists still do not understand the process of losing motor neurons in ALS ALS is known for genetic heterogeneity – which means that there are many possible combinations of genes and factors that can lead to als. This makes it difficult to develop a single treatment that works for everyone.”

Yasuaki Watanabe, assistant professor, Tohoku University

For example, the feature of many ALS cases is the loss of TDP-43 (nuclear RNA binding protein), which causes universal dilation of RNA. However, many other proteins associated with ALS were also involved, such as FUS, Matr3 and Hnrnpa1, each with different pathological mechanisms. This variety has long made it difficult to search for typical therapeutic goals.

Leaded by the assistant Professor Yasuaki Watanabe and Professor Keiko Nakayam, the University of Tohoku, the band tried to identify the molecular path divided between different forms of ALS. They generated neural cellular lines in which one of the four key proteins binding RNA ALS were exhausted. In all cases, UNC13A expression has been significantly reduced.

The study revealed two separate molecular mechanisms underlying this reduction. One mechanism includes the inclusion of a mysterious exon into the UNC13A transcription, which leads to MRNA destabilization. The second was a completely new discovery, which shows that the loss of FUS, MATR3 or HNRNPA1 causes the overexpression of the relaxation of the transcription repressor. As the name suggests, Rest suppresses the transcription of the UNC13A gene, thanks to which it is not able to usually perform helpful functions. This attenuation can be what leads to symptoms found in ALS.

To explain whether these results reflected what really took place in patients with ALS, scientists looked at motor neurons derived from IPS cells of the ALS patient and spinal cord tissues from ALS autopsy cases. Importantly, scientists confirmed increased resting levels, strengthening the clinical significance of their results.

This newly discovered convergence of separate mutations causing ALS to a single effect below-NUNC13a-ofs Critical Insight in the complexity of the disease. The results emphasize UNC13A as central hubs in ALS pathogenesis and suggest that maintaining its expression or modulating resting activity can represent promising therapeutic strategies.

“This study is a valuable framework for the development of a wide spectrum treatment, which directed joint molecular gaps in ALS,” says Nakayama.

As ALS progresses, the patients’ muscles are wasted until they finally lose their ability to swallow or breathe. Treatment that can potentially slow down or prevent this progression in as many patients as possible is a large step forward in ALS research.