TDP-43: What It Is and Why It Matters in ALS
TDP-43 is a protein found in cells throughout the body and has become a major focus of ALS research. It normally resides in the nucleus, the part of the cell that houses genetic material. It normally moves between the nucleus and the cytoplasm to manage the genetic instructions cells rely on to function.
September 16, 2026
In nearly 97% of ALS cases, TDP-43 leaves the nucleus and remains in the cytoplasm in an abnormally clumped form, making it one of the most consistent biological clues scientists have for understanding what goes wrong inside cells affected by the disease.
What happens to TDP-43 in ALS?
In most ALS cases, TDP-43 moves out of the nucleus, mislocalizes in the cytoplasm (the area surrounding the nucleus inside the cell) in the form of abnormal clumps.
This creates two problems that researchers are working to understand. When TDP-43 leaves the nucleus, it can no longer perform its normal functions there. At the same time, abnormal TDP-43 accumulates in the cytoplasm, forming clumps that may be toxic and/or lead to disruption of processes motor neurons need to function and survive.
Why does TDP-43 matter in ALS research?
ALS does not have a single cause. Different genetic and biological factors can contribute to the disease, yet TDP-43 abnormalities appear across nearly all of them, in both non-genetic and genetic forms.
That consistency suggests that different forms of ALS, despite their distinct origins, may share some underlying biology. Understanding what happens to TDP-43 and what happens in cells when it stops functioning normally could reveal biological processes relevant to a broad range of people living with the disease.
What are researchers studying?
Why TDP-43 leaves the nucleus but remains stuck in the cytoplasm remains one of the biggest open questions in ALS research. Scientists are working to understand what sets this process in motion, and whether it can be interrupted or reversed.
At the same time, scientists are investigating ways to restore cellular processes disrupted when TDP-43 no longer functions normally and are also developing biomarkers to detect signs of TDP-43 dysfunction in people living with ALS. Because TDP-43 pathology occurs inside cells, it is difficult to directly measure TDP-43 dysfunction. Reliable biomarkers could eventually help researchers identify changes in TDP-43 function and determine whether potential treatments are having their intended effect.
Together, these approaches are helping researchers move from understanding TDP-43 as a hallmark of ALS to asking how that knowledge might be used to develop and evaluate new treatments.
How is Target ALS advancing TDP-43 research?
Target ALS supports research to understand TDP-43 across the full arc of discovery, from uncovering its basic biology to developing potential therapeutic approaches and biomarkers.
Through collaborative research programs, Target ALS brings together scientists from different institutions and disciplines to investigate questions about TDP-43 that no single laboratory could answer alone. Target ALS provides researchers with access to shared resources, including human tissue, biofluids, reagents, and stem cells that can help them test hypotheses and build on each other’s findings.
TDP-43 remains a central focus of the Target ALS Basic Biology Consortia Program. In 2026, funded collaborative teams are investigating what causes TDP-43 to leave the nucleus, how its dysfunction affects other cells and biological systems, and what those changes could reveal about potential therapeutic targets and biomarkers.
Findings from basic biology research can also help inform the next stages of discovery. Target ALS’s 2026 In Vivo Target Validation Programs use a TDP-43 mouse model of ALS to evaluate potential therapeutic targets and generate evidence that can inform future therapeutic development.
Related News
What are biomarkers in ALS research?
September 16, 2026
Building the Data Foundation for AI-Driven ALS Drug Discovery
August 25, 2026
Brenda Bucklin's Story: Living with C9-ALS
August 10, 2026