UC San Diego researchers find a key pathway to ALS

Last Updated on May 1, 2025

The findings point to the potential for short-circuiting the progression of the fatal disease if diagnosed early.

Researchers from UC San Diego and their colleagues have identified a key pathway that sets off neurodegeneration in the early stages of amyotrophic lateral sclerosis (ALS), a fatal disease with no cure.

The findings could lead to development of therapies to prevent or slow the progression of ALS early on, before major damage has been done, according to the study, published on Oct 31 in Neuron.

Approximately 5,000 people in the US develop ALS each year; on average, they survive for only two to five years after being diagnosed, according to the Centers for Disease Control and Prevention. The rapidly progressing neurodegenerative disease causes the death of neurons in the brain and spinal cord, resulting in muscle weakness, respiratory failure and dementia.

Little is known about what first triggers the deterioration of motor neurons at the onset of ALS, signified by the accumulation of a protein called TDP-43 in the cytoplasm, outside its usual location in the nucleus of motor neurons.

“By the time you see a patient with ALS and you see the TDP-43 protein aggregated in the cytoplasm, it’s like the accident site with all the cars crashed already, but that’s not the initiating event,” corresponding author Gene Yeo, professor in the Department of Cellular and Molecular Medicine at the UCSD School of Medicine and director of the Center for RNA Technologies and Therapeutics and the Sanford Stem Cell Institute Innovation Center, said in a press release.

Tracing the events leading up to the “accident”, Yeo explains that another protein, called CHMP7 — normally found in the cytoplasm — builds up in the nucleus instead, setting off a cascade of events that ultimately lead to motor neuron degeneration. But what causes CHMP7 to accumulate in the nucleus to begin with?

Yeo and his team screened for RNA-binding proteins that might influence CHMP7 build-up in the nucleus. This yielded 55 proteins, 23 of which had a potential connection to ALS pathogenesis. Inhibiting the production of several of these proteins led to an increase in CHMP7 in the nucleus.

A build-up of CHMP7 in the nucleus damages nucleoporins, which Yeo likens to tiny portals in the membrane separating the nucleus from the cytoplasm that orchestrate the movement of proteins and RNA between the two cellular spaces. Dysfunctional nucleoporins allow TDP-43 to exit the nucleus and accumulate in the cytoplasm. Once there, the protein can no longer oversee the gene expression programs necessary for neurons to function.

However, when the researchers boosted SmD1 expression in cells, CHMP7 was restored to its usual location in the cytoplasm, leaving nucleopores intact, allowing TDP-43 to stay in the nucleus, thus sparing the motor neurons from degeneration.

The discovery is intriguing as “there are actually therapeutics for spinal muscular atrophy,” Yeo said. “One of them, risdiplam, is a small molecule compound that enhances the splicing and expression of SMN2, a gene closely related to the SMN1 gene that becomes dysfunctional in ALS.”

This hints at the possibility that using risdiplam to raise SMN levels could prevent ALS from developing past the earliest stage of the disease.

The next steps will be to raise funds to continue the research in animal models and in other genetic models of ALS, and eventually test the effectiveness of risdiplam or other compounds for short-circuiting ALS.