They identify a key trigger for neurodegeneration in the early stages of ALS.

Amyotrophic lateral sclerosis (ALS), a rapidly progressive neurodegenerative disease, causes the death of neurons in the brain and spinal cord, leading to muscle weakness, respiratory failure and dementia. Despite the devastating nature of the disease, little is known about what causes motor neuron deterioration early in the disease.

Now a group of researchers from the University of California, San Diego (USA) has been able to identify a key pathway that triggers neurodegeneration in the early stages of the disease. The findings could lead to the development of treatments to prevent or slow the progression of ALS early on, before significant damage is done.

The study, published in the journal Neuron, reports that a protein called TDP-43 is typically found in the nuclei of motor neurons, where it regulates the expression of genes essential for cell function. TDP-43 accumulating in the cytoplasm outside the nucleus has been shown to be a hallmark feature of ALS. Until now, researchers have not been able to understand how the protein ends up in the wrong place, causing neuronal degeneration.

“When a patient with ALS has the TDP-43 protein aggregated in the cytoplasm, it is comparable to the location where a traffic accident occurs, when all the vehicles are hit together,” said the author, Prof. Jean Yeo is from the Department of Cellular and Molecular Medicine at the University of California San Diego School of Medicine and director of the Center for RNA Technologies and Therapeutics and the Innovation Center at the Sanford Stem Cell Institute.

The authors of the work looked for proteins that bind to RNA and can influence the accumulation of CHMP7 in the nucleus. As a result, 55 proteins were discovered, 23 of which were potentially related to the pathogenesis of ALS. Inhibition of the production of some of these proteins resulted in an increase in CHMP7 in the nucleus. Subsequent experiments with motor neurons generated from induced pluripotent stem cells derived from ALS patients led to the surprising discovery that deletion of one of them, an RNA splicing-associated protein called SmD1, which until now had no known effect on CHMP7 levels had the greatest effect. increasing its nuclear accumulation.

The accumulation of CHMP7 in the nucleus damages nucleoporins, which they likened to small portals in the membrane separating the nucleus from the cytoplasm and orchestrating the movement of proteins and RNA between the two cellular spaces. Dysfunctional nucleoporins allow TDP-43 to leave the nucleus and accumulate in the cytoplasm. Once there, the protein can no longer control the gene expression programs needed for neurons to function.

However, when the researchers increased the expression of SmD1 in the cells, CHMP7 returned to its normal location in the cytoplasm, leaving the nucleopores intact and allowing TDP-43 to remain in the nucleus, thereby preventing motor neuron degeneration.

“You can actually localize this CHMP7 protein and therefore all the downstream effects,” said Nora Al-Azzam, the study’s first author, then a neurobiology student in Yeo’s lab who will receive her PhD in spring 2024.

In addition, the SmD1 protein is part of the SMN multiprotein complex, the dysfunction of which is associated with another neurodegenerative disease: spinal muscular atrophy.

These researchers suspect that the SMN complex may play a critical role in amyotrophic lateral sclerosis, but they believe further research is needed to confirm this.