Approximately 5,000 new cases of amyotrophic lateral sclerosis (ALS) are diagnosed each year in the United States. ALS, a rapidly progressing neurodegenerative disease, is marked by the progressive death of motor neurons in the brain and spinal cord. This leads to debilitating muscle weakness, respiratory failure, and in some cases, cognitive decline or dementia. Individuals diagnosed with ALS typically survive only two to five years on average after diagnosis. While much is known about the progression of ALS symptoms, the biological mechanisms that trigger motor neuron degeneration in the early stages of the disease have remained largely elusive.
Recent research conducted by scientists at the University of California, San Diego (UCSD) has identified a molecular pathway that may be responsible for initiating neurodegeneration in the early phases of ALS. These findings, published in Neuron on October 31, 2024, could open doors for new therapies designed to halt or slow the progression of ALS before irreversible damage occurs. By targeting the newly identified pathway, researchers hope to offer potential interventions that could significantly improve outcomes for ALS patients.
A central focus of the study is a protein known as TDP-43. In healthy motor neurons, TDP-43 is typically located within the cell nucleus, where it plays a critical role in regulating gene expression needed for neuron function. However, in ALS patients, TDP-43 has been found to accumulate in the cytoplasm—outside of the nucleus—a mislocation that has become a defining hallmark of ALS pathology. While researchers have known about the cytoplasmic accumulation of TDP-43 for years, the exact mechanisms causing this displacement have remained unclear. According to Gene Yeo, Ph.D., lead researcher and professor in UCSD’s Department of Cellular and Molecular Medicine, the accumulation of TDP-43 in the cytoplasm is more of a consequence than an initiating event in ALS. The study sought to trace the molecular steps that lead to this abnormal protein localization.
The researchers discovered that another protein, called CHMP7, may be responsible for setting off the cascade of events that eventually results in TDP-43’s mislocalization and motor neuron degeneration. Unlike TDP-43, CHMP7 is normally found in the cytoplasm under healthy conditions. However, in early ALS, CHMP7 begins to accumulate within the nucleus. This abnormal buildup appears to be a critical initiating factor in the disease’s pathology, leading to cellular dysfunction and eventually neurodegeneration. The research team wanted to understand what causes CHMP7 to relocate to the nucleus, where it begins to interfere with neuronal function.
To investigate further, the team conducted a screen for RNA-binding proteins that could potentially influence the nuclear buildup of CHMP7. They identified 55 proteins with possible roles in ALS, of which 23 had direct links to ALS pathogenesis. The researchers found that inhibiting the production of certain proteins among these candidates led to increased accumulation of CHMP7 within the nucleus. One protein, in particular, stood out—SmD1, an RNA-splicing protein previously unassociated with CHMP7 regulation, was found to have the most significant effect on CHMP7 nuclear accumulation when depleted.
Further experiments using motor neurons derived from ALS-patient cells provided additional insights. The team found that reducing SmD1 levels led to a dramatic buildup of CHMP7 in the nucleus, which in turn affected nucleoporins—key proteins that form channels or “nuclear pores” in the membrane between the nucleus and cytoplasm. Nucleoporins control the movement of proteins and RNA in and out of the nucleus, so when these channels are compromised, proteins like TDP-43 can escape into the cytoplasm, leading to the disruption of critical gene expression processes needed for motor neuron survival.
The researchers then explored whether they could prevent CHMP7 from accumulating in the nucleus by restoring SmD1 levels. When they increased SmD1 expression, CHMP7 was retained in the cytoplasm, allowing the nucleoporins to function normally. This, in turn, kept TDP-43 inside the nucleus, where it could continue its gene-regulating role, thus preventing motor neuron degeneration.
SmD1 is a component of a larger multiprotein complex called SMN (survival of motor neuron), known to be implicated in spinal muscular atrophy (SMA), another neurodegenerative disease. Notably, SMA treatment approaches have made significant progress with therapies targeting SMN, including a drug called risdiplam. Risdiplam functions by enhancing the splicing and expression of SMN2, a gene closely related to the SMN1 gene affected in ALS. Given the similarities between ALS and SMA in terms of SMN’s role, Yeo and his team are hopeful that risdiplam or similar compounds could be repurposed to prevent ALS from advancing past its earliest stages by boosting SMN levels and stabilizing SmD1 function.
This breakthrough offers a promising therapeutic direction: if clinicians could intervene at the first signs of ALS symptoms and halt further motor neuron damage, they might prevent the rapid spread of neurodegeneration throughout the central nervous system. The findings suggest that ALS does not cause all motor neurons to fail simultaneously; rather, certain neurons die first, and the degeneration then spreads to neighboring neurons. An early intervention aimed at maintaining nuclear function and TDP-43 localization could theoretically keep many motor neurons intact, thereby slowing or even halting ALS progression.
The research team is now exploring the potential of this approach in animal models of ALS and in other genetic models to verify if the SMN pathway plays a definitive role in ALS onset. They hope to secure funding to further test risdiplam and other compounds that might correct SMN and SmD1 dysfunctions in ALS patients. If successful, this approach could represent a new frontier in ALS treatment, potentially transforming a diagnosis that is currently a death sentence into one with a far better prognosis.