How the Immune System May Drive ALS: Two Miami Researchers Explore New Clues

By: Jodie Nicotra | August 26, 2026 | 8 min. read |

Two University of Miami Miller School of Medicine postdoctoral researchers are examining how immune responses triggered by TDP-43 dysfunction may contribute to ALS, opening potential paths toward earlier detection and new treatments.

Portrait of Dr. Leonard Petrucelli wearing a navy blazer and light blue collared shirt against a neutral gray background.

For years, scientists have known that immune cells are present in the nervous systems of people with amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease). But it remains unclear what draws those immune cells to the brain and spinal cord and exactly how they contribute to the death of motor neurons.

Two University of Miami Miller School of Medicine postdoctoral researchers are approaching that mystery from different angles. Eurus Wang, M.D., Ph.D., and Wangchen Tsering, Ph.D., are investigating how changes inside ALS-affected cells might trigger an immune response and what those immune cells do once they arrive.

Their research is supported by Milton Safenowitz postdoctoral fellowships from the ALS Association, which provides early-career researchers with two years of financial support as well as opportunities for training, networking and sharing research.

Why This Research Matters

Amyotrophic lateral sclerosis (ALS) remains one of the most devastating neurodegenerative diseases, with limited treatment options and no cure. Scientists have long known that immune cells appear in the nervous systems of people with ALS, but they are still working to understand why those cells arrive and what role they play in disease progression.

By investigating how TDP-43 dysfunction may trigger immune responses and using cutting-edge technologies to study immune activity within intact brain tissue, University of Miami researchers hope to reveal new biological pathways involved in ALS. These discoveries could eventually support earlier diagnosis, identify new therapeutic targets and improve outcomes for people living with the disease.

A former Safenowitz fellow, Mercedes Prudencio, Ph.D., associate professor of biochemistry and molecular biology at the Miller School, knows firsthand how receiving such an award early in one’s career can shape a research trajectory.

She said, “I am so proud that both Dr. Wang and Dr. Tsering have been awarded such prestigious fellowship. I am confident it will serve as an equally powerful catalyst for their scientific development.”

Searching for a Cellular Safeguard Against ALS

A new member of Dr. Prudencio’s laboratory, Dr. Wang plans to study an ALS immune mechanism related to loss of normal function of a regulatory protein called TDP-43.

“In normal cells, TDP-43 acts as a control to help prevent hidden, disruptive gene sequences called cryptic exons from being mistakenly included in RNA, so that cells produce the correct proteins,” Dr. Wang said. “In ALS, TDP-43 loses this normal function.”

This failure of TDP-43 can lead the cell to produce novel protein sequences called cryptic peptides. These peptides are not normally produced by healthy cells. They may appear foreign to the immune system, leading to an immune response that may contribute to the damage and death of affected neurons, which is a key feature of ALS.

Dr. Wang’s study focuses on a different protein, called hnRNP L. That protein can step in and partially compensate when TDP-43 loses function, acting as a sort of cellular safeguard against the production of cryptic peptides. Thus, Dr. Wang hypothesizes, hnRNP L could potentially be used therapeutically in patients with ALS. If researchers can find ways to increase or support hnRNP L activity when TDP-43 function is lost, it may help reduce abnormal protein production and the resulting immune response.

“I always think that, when it comes to disease, prevention is better than cure,” she said. “I would love to find a simple blood test for a molecule or protein that would help us know if a patient has a higher risk for ALS, so that we could do something at that point to prevent it.”

Frequently Asked Questions

What role does the immune system play in ALS?

Researchers have long observed immune cells in the brains and spinal cords of people with ALS, but scientists still do not fully understand what attracts those cells or whether they contribute to motor neuron damage. The studies led by Safenowitz fellows Eurus Wang, M.D., Ph.D., and Wangchen Tsering, Ph.D., aim to answer those questions.

What is TDP-43 and why is it important in ALS?

TDP-43 is a protein that helps cells process genetic information correctly. In many cases of ALS, the protein loses its normal function, which can trigger a cascade of biological changes that may contribute to neurodegeneration and immune activity within the nervous system.

What are cryptic peptides?

Cryptic peptides are abnormal protein fragments that may be produced when TDP-43 loses its normal function. Because healthy cells typically do not produce these peptides, researchers believe they may appear foreign to the immune system and potentially provoke an immune response.

What is spatial transcriptomics?

Spatial transcriptomics is an advanced technology that allows researchers to map gene activity while preserving the physical location of cells within tissue. This helps scientists understand how different cell types interact within diseased areas of the brain and spinal cord.

Could this research lead to new ALS treatments?

The goal of both projects is to better understand the biological processes that drive ALS. By identifying how immune responses develop and affect neurons, researchers hope to uncover opportunities for earlier diagnosis and future therapies that could slow disease progression.

Mapping Immune Activity Inside Diseased Brain Tissue

Dr. Tsering’s research also focuses on the TDP-43 pathology in ALS. Dr. Tsering, who belongs to the laboratory headed by Leonard Petrucelli, Ph.D., professor in the Department of Neurology and founding director of the Neuroscience Institute at the Miller School, draws on his previous experience in a neuropathology lab studying human brain tissues with sophisticated technologies.

To study the immune system response to the failure of TDP-43, Dr. Tsering’s project uses single-cell spatial transcriptomics, a technology that maps gene activity inside intact tissue. While traditional methods break apart cells and hence lose the map, spatial transcriptomics keeps the cellular tissue intact, showing both which genes are turned on and the exact physical location of the cells in the tissue.

“In a disease context, the neighborhood matters. It’s not just what’s happening inside a single cell,” Dr. Tsering said. “My biggest question here is how can we leverage brain tissue, first using these sophisticated technologies to truly understand it and then manipulate it in a model system, rather than trying to use a model system to try to predict what’s there.”

Using single-cell spatial transcriptomics, Dr. Tsering hopes to find out whether T cells are actively attacking neurons or if they’re simply accumulating and acting as bystanders. Understanding what the cells are doing could increase the potential for timely therapeutic intervention.

“I’m coming from research on Alzheimer’s disease, which patients can live with for a number of years,” he said. “But for patients with ALS, the window of opportunity to target it is a lot shorter, so the work seems especially urgent. If we can figure out the driver of neurodegeneration, that could help a lot. Even if we can’t cure it, we might be able to modify the disease quite a bit in order to expand the lifespan in those patients. That’s the promise.”