When brain cells die in diseases like ALS (amyotrophic lateral sclerosis) and frontotemporal dementia, they often activate a "self-destruct" program called apoptosis. Now, researchers in the Pulst-Scoles Laboratory in the Department of Neurology at the University of Utah have discovered a promising new way to protect neurons from this harmful process by targeting a protein called STAUFEN-1.
The findings, published in the journal Cell Death & Disease, could lead to new treatments for multiple neurodegenerative diseases, including ALS, Parkinson's disease, and Alzheimer's disease.
How Neurons Die in ALS and Neurodegenerative Diseases: The Role of p53 and DNA Damage
Mandi Gandelman, MSci, PhD, the study's first author, has dedicated her career to understanding neuron death in neurodegenerative diseases. "I study how and why neurons die during these diseases, what triggers them to die, and how can we prevent this," Gandelman explained.
The challenge is particularly urgent because more than 90% of neurodegenerative diseases are not inherited. "We need to find out how the neurons say, 'I'm getting signals that I need to die,' and intervene at that point," Gandelman said.
One of the main triggers for neuron death is a cellular pathway controlled by a protein called p53. When activated by stress or damage, p53 can tell neurons to die when they shouldn't, accelerating disease progression. Gandelman and her colleagues discovered that a protein called STAUFEN-1, which becomes abnormally elevated in multiple neurodegenerative diseases, plays a crucial role in this deadly process.
Testing STAUFEN-1 Reduction in Human Neurons and Brain Cells
The research team used multiple experimental approaches, starting with human neurons created from induced pluripotent stem cells. "We call them iPSC-derived neurons," Gandelman explained. "We can differentiate them into neurons, and then we can study neurons in a dish."
Using human neurons was crucial. "When we have a finding, we want to make sure we can translate that to patients," Gandelman noted.
The researchers first analyzed gene expression when STAUFEN-1 levels were reduced and found that over 3,000 genes changed their activity, with many cell death genes being turned down. Then came the critical experiments: exposing neurons to compounds that activate p53 and normally cause extensive cell death.
One compound, etoposide, causes DNA breaks. "The cells try to repair these breaks, and usually when we add enough of this compound, they cannot repair those breaks, and they just all die massively," Gandelman explained.
But when STAUFEN-1 levels were reduced, something remarkable happened: "If we lower STAUFEN-1, DNA damage is prevented and they survive."
The protection was dramatic. "These compounds cause very extensive DNA damage and cell death in neurons unless we intervene on STAUFEN-1. This is important because such breaks are very common in all neurodegenerative diseases," Gandelman noted.
What Are iPSC-Derived Neurons and Why They Matter for ALS Research
iPSC-derived neurons are human brain cells grown in the lab from reprogrammed adult cells. Scientists use them as a "brain-in-a-dish" to study brain diseases like ALS and Parkinson's disease, test new medicines, and learn how the human brain works. These lab-grown neurons can behave like real nerve cells by forming connections and sending signals. Researchers are now working to make these models more realistic by growing networks of different brain cell types, such as support and immune cells, to better mimic what happens in the human brain.
ALS Mouse Models Confirm STAUFEN-1 Reduction as a Promising Therapeutic Strategy
To ensure their findings were not limited to laboratory conditions, the researchers tested mice carrying a C9orf72 mutation, one of the most common genetic causes of ALS. These mice accumulate DNA damage over their lifespan.
The team bred these disease mice with mice that have lower STAUFEN-1 levels. The results mirrored the human neuron experiments: the p53 death pathway was less activated.
"We show that this works in human neurons and that this also works with the triggers of neuronal death in the mouse," Gandelman said. "That gives us a good answer of how this could be valuable for therapeutics."
From Discovery to Therapy: Advancing STAUFEN-1 Treatments Toward ALS Clinical Trials
"In many neurological diseases, STAUFEN-1 abundance goes up," Gandelman explained. "And also, we see that many of those diseases have increased levels of DNA damage. Here, we described how reducing those elevated levels of STAUFEN-1 prevents DNA damage."
The lab is now developing therapeutic molecules for clinical trials. Daniel Scoles, PhD, is screening antisense oligonucleotides, molecules that can degrade STAUFEN-1 RNA and reduce STAUFEN-1 levels in the nervous system.
Because STAUFEN-1 is elevated in multiple neurodegenerative diseases, this approach could potentially help patients with ALS, Parkinson's, Alzheimer's, and other conditions where DNA damage drives neurodegeneration.
