Researchers have discovered a crucial pathway that may lead to neurodegeneration in the initial phases of ALS, suggesting an early diagnosis could help halt the disease’s severe progression.
Each year, around 5,000 individuals in the U.S. are diagnosed with amyotrophic lateral sclerosis (ALS). The average lifespan post-diagnosis is a mere two to five years, according to the Centers for Disease Control and Prevention. This fast-moving neurodegenerative condition leads to neuron destruction in the brain and spinal cord, causing symptoms such as muscle weakness, breathing difficulties, and cognitive decline. Unfortunately, the initial triggers for the deterioration of motor neurons at the onset of ALS remain largely unclear.
Researchers from the University of California, San Diego, along with their collaborators, recently announced that they have pinpointed a significant pathway that initiates neurodegeneration in the early stages of ALS. Their findings could pave the way for creating therapies aimed at preventing or slowing the disease’s progress if diagnosed in its early phases. This research was published on October 31, 2024, in Neuron.
In healthy motor neurons, a protein known as TDP-43 typically resides in the nucleus, where it regulates essential gene expression. However, its accumulation in the cytoplasm, outside the nucleus, is a hallmark of ALS. The reason behind TDP-43’s misplacement, which leads to neuron degeneration, has puzzled scientists until now.
Gene Yeo, Ph.D., a professor in the Department of Cellular and Molecular Medicine at UC San Diego School of Medicine and director of the Center for RNA Technologies and Therapeutics, explained, “When you see TDP-43 aggregated in the cytoplasm of a patient with ALS, it’s like showing up at an accident scene after everything has already happened; this event isn’t what triggered the issue in the first place.”
To understand what occurs before this “accident,” Yeo states that another protein, CHMP7—usually found in the cytoplasm—uncharacteristically builds up in the nucleus, triggering a series of events that lead to the degeneration of motor neurons. But what causes this initial accumulation of CHMP7 in the nucleus?
Yeo’s team investigated RNA-binding proteins that might play a role in the nuclear buildup of CHMP7. They identified 55 proteins, of which 23 were associated with ALS development. Suppressing the production of several of these proteins led to increased levels of CHMP7 in the nucleus. Further experiments involving motor neurons derived from induced pluripotent stem cells of ALS patients surprisingly revealed that reducing levels of an RNA-splicing protein called SmD1—previously unknown to impact CHMP7—resulted in the most significant increase in CHMP7 accumulation in the nucleus.
The accumulation of CHMP7 in the nucleus damages nucleoporins, which are likened to tiny gateways in the membrane separating the nucleus from the cytoplasm, controlling protein and RNA movement between these two spaces. Impaired nucleoporins enable TDP-43 to exit the nucleus and cluster in the cytoplasm, where it can no longer manage the gene expression needed for neuron functionality.
However, when the researchers enhanced SmD1 levels in the cells, CHMP7 was returned to its typical cytoplasmic location, preserving nucleoporins and allowing TDP-43 to remain in the nucleus, protecting motor neurons from deterioration.
“We can effectively correct the misplaced CHMP7 protein, which would mitigate all related downstream effects,” said Norah Al-Azzam, the study’s first author, a former neurosciences student in the Yeo lab who completed her Ph.D. in spring 2024.
Moreover, the SmD1 protein is part of the SMN complex, which is associated with another neurodegenerative disease, spinal muscular atrophy (SMA).
“This is interesting because there are already treatments available for SMA,” Yeo remarked. “For instance, risdiplam is a small molecule that promotes splicing and expression of the SMN2 gene, which relates closely to the dysfunctional gene in ALS.”
This raises the potential that using risdiplam to elevate SMN levels might prevent ALS from progressing beyond its earliest stages.
“Neurons don’t all fail at once,” Yeo explained. “Some neurons start to die before others. If we treat a patient as soon as symptoms appear, we might be able to save remaining neurons and halt ALS progression.”
The researchers believe the SMN complex may be vital in ALS’s onset, but further studies are necessary. Their next steps will involve raising funds to explore this in animal models and other genetic models of ALS, eventually testing the effectiveness of risdiplam or similar compounds to intervene in ALS early on.
Additional co-authors on this study include: Jenny H. To, Vaishali Gautam, Dylan C. Lam, Chloe B. Nguyen, Jack T. Naritomi, Assael A. Madrigal, Benjamin Lee, Anthony Avina, Orel Mizrahi, Jasmine R. Mueller, Willard Ford, Anthony Q. Vu, Steven M. Blue, Yashwin L. Madakamutil, Uri Manor, Cara R. Schiavon, and Elena Rebollo, all from UC San Diego; Wenhao Jin from Sanford Laboratories for Innovative Medicines; Lena A. Street and Marko Jovanovic from Columbia University; Jeffrey D. Rothstein and Alyssa N. Coyne from Johns Hopkins University School of Medicine.
This research received partial funding from the National Institutes of Health (grants R01HG004659, U24 HG009889, R35GM128802, R01AG071869, and R01HG012216), the National Science Foundation (MCB-2224211), and the Chan-Zuckerberg Initiative.
