Temple University researchers find ATF2 protein as a central driver in the chain reaction behind cell death and how interrupting it could protect the brain.

Imagine a row of dominoes. When one falls, the result is a long cascade as each domino topples over. Scientists at Temple University’s Lewis Katz School of Medicine, in collaboration with the National Institutes of Health, have found that a protein in neurons acts in a similar way.  

In the new study, Jorge Gomez-Deza, assistant professor of cancer and cellular biology at Katz, discovered that a protein in neurons called ATF2 plays a much larger role than previously thought in the cell death process. Gomez-Deza served as a corresponding author of the study, “ATF2 phosphorylation is a core transcriptional driver of neuron apoptosis,” published online on May 19 in Neuron, a leading peer-reviewed journal in the field of neuroscience published by Cell Press.

“This finding helps us better understand the process that causes cell death and how we may be able to prevent it in the future,” said Gomez-Deza.

The focus of Gomez-Deza’s lab is understanding how neurons are damaged in response to chemotherapy, particularly in children. However, his research is widely applicable to neurodegenerative conditions such as glaucoma, traumatic brain injury and amyotrophic lateral sclerosis.   

“My lab is particularly interested in how this pathway contributes to chemotherapy-induced nerve damage and pain, especially in children receiving certain cancer treatments,” said Gomez-Deza. “We are deeply interested in uncovering new molecular mechanisms that drive neuron death to be able to develop novel therapeutic strategies. Because chemotherapy is delivered on a predictable schedule, we believe it may be possible one day to treat patients beforehand to protect neurons from damage.”

To better understand how neuron death occurs across these conditions, Gomez-Deza investigated the molecular signaling pathways that trigger degeneration. Cell death can occur for a variety of reasons, including traumatic brain injury, neurodegenerative diseases and chemotherapy. When neurons are injured or stressed—due to disease or trauma—a chain reaction of molecular signals occurs. The study found that, like a domino, ATF2 triggers the pathway that activates this chain reaction of apoptosis, or cell death. The research builds on the broader Dual Leucine Zipper Kinase (DLK) signaling pathway that was already well known in neuron death.

“Although ATF2 itself may be difficult to directly target with drugs, identifying it as a central node in the degeneration pathway opens new opportunities to design therapies that block its interactions with other proteins and interrupt the signaling cascade that leads to neuron death,” explained Gomez-Deza.

To home in on ATF2’s role, Gomez-Deza used genetic screening to scan the entire human genome. Using CRISPR—a gene-editing technology that acts like a pair of molecular scissors, allowing scientists to precisely modify DNA—researchers silenced one gene at a time in each neuron to identify the key drivers of cell death. When Gomez-Deza silenced ATF2, the cascade of cell death was interrupted, and brain cells were protected and survived. 

Silencing ATF2 in neurons and exposing them to chemotherapy protects the cells as well. Typically, neurons die when exposed to chemotherapy. Many patients who undergo chemotherapy have pain as the drugs damage or destroy peripheral nerves, which is known as chemotherapy-induced peripheral neuropathy. In this study, Gomez-Deza silenced ATF2, then added chemotherapy, and discovered that neurons survived. This finding shows that ATF2 is driving neurodegeneration in response to chemotherapy treatment.

Gomez-Deza also tested the pathway in other experimental models. For example, in an optic nerve injury model like glaucoma, he found that silencing ATF2 improved neuron survival, suggesting that ATF2’s role may be relevant across multiple types of neural injury. The results demonstrated that understanding ATF2’s larger role in cell death could lead to new treatments that help prevent brain-cell loss in a wide range of neurodegenerative diseases.