Shared protein pathology redefines treatment for multiple neurodegenerative diseases

On the surface, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE) might seem like unrelated diseases. ALS destroys motor neurons, causing muscle weakness and eventually paralysis. FTD hits the brain's frontal and temporal lobes, affecting language, personality and behavior. LATE is a slowly progressing memory disorder that resembles Alzheimer's disease and tends to affect people over 85. 

But for all these distinctions, ALS, FTD and LATE share an important biological foundation, a protein called TDP-43. This commonality is generating an important question: Should we place greater emphasis on a disease's biological underpinnings than we do on its symptoms and other traits (phenotypes)?

To help answer this question, a large international group of clinicians, researchers and others, led by Michael Benatar, M.D., Ph.D., the Walter Bradley Chair in ALS Research and Executive Director of the ALS Center at the University of Miami Health System and the Miller School, have authored a paradigm-shifting review. 

Published in JAMA Neurology on August, 24th, the paper titled "TDP-43-Associated Neurodegenerative Disease Conceptualization and Integrated Staging" dives into TDP-43's relationship with ALS, FTD, LATE and other severe neurodegenerative conditions, coining the term TDP-43 associated neurodegenerative disease (TAND) to describe these relationships. Viewing these diseases through a biological lens could profoundly impact biomarker research, clinical trials and eventually clinical care.

Historically, we've thought about a disease based on its phenotype. But we now think they should be defined by their underlying biology. The phenotypes are simply manifestations of that disease biology. We don't want to do away with clinically useful terms, such as ALS and FTD, but we need to see them for what they are."

Michael Benatar, M.D., Ph.D., the Walter Bradley Chair in ALS Research and Executive Director of the ALS Center, University of Miami Health System and the Miller School

TDP-43's job is quality control

While TDP-43 may have several functions, its main role is regulating a ubiquitous biological mechanism called RNA splicing. When a gene expresses RNA (which is eventually translated into a protein), that RNA can be put together (spliced) in different ways. This allows one gene to make similar but distinct forms of the same protein. 

TDP-43 helps oversee this process to prevent mistakes. Unfortunately, in ALS, LATE and around half of FTD cases, TDP-43 cannot perform this task, leading to aberrant RNA splicing. As a result, cells generate abnormal forms and quantities of proteins. This central role in splice regulation may explain why TDP-43 is relevant to so many neurodegenerative conditions.

"Hundreds of genes rely on TDP-43 for proper splicing," said Sami Barmada, M.D., Ph.D., the Angela Dobson Welch and Lyndon Welch Research Professor at the University of Michigan and a co-author on the review. "To do this job (RNA splicing), TDP-43 must be in the nucleus, but in disease, TDP-43 instead builds up in the cell's cytoplasm. It is this combination of TDP-43's absence from the nucleus and its accumulation in the cytoplasm (TDP pathology) that may be critical for disease."

Rethinking therapeutic development

TAND is a different way to think about neurodegenerative conditions, but it's far more than a philosophical construct. This common link between ALS, FTD, LATE and other diseases could profoundly impact drug development.

"If somebody has ALS with TDP-43 pathology, and another person has FTD with TDP-43 pathology, the same treatment will likely work in both people," said Corey McMillan, Ph.D., associate professor of Neurology, co-director of the FTD Center at the Perelman School of Medicine at the University of Pennsylvania and co-author on the review. "It makes no sense to develop separate TDP-43-targeting therapies for each disease."

By looking holistically at the different diseases TDP-43 influences, biopharma companies could more efficiently develop drugs that impact multiple conditions. This could be particularly helpful for people with rare conditions, such as multisystem proteinopathy, who have virtually no therapeutic options and could potentially benefit from TDP-43-focused medicines. 

"This is an especially important insight for ultra-rare forms of disease that are associated with TDP-43 pathology," explained Edward Lee, M.D., Ph.D., the John Q. Trojanowski, M.D., Ph.D., professor for Neurodegenerative Disease Research at the Perelman School of Medicine at the University of Pennsylvania and review co-author.

This could also impact clinical trials. FTD patients can have two distinct pathologies, one based on TDP-43 dysfunction and another driven by tau protein accumulation. While FTD-TDP-43 patients would likely respond to a TDP-43-focused treatment, FTD-tau patients would not respond at all. 

This underscores the importance of understanding the biology of each person's disease to effectively populate clinical trials, but there's another layer. Monitoring TDP-43 could potentially help clinicians recognize ALS, FTD and other conditions long before symptoms appear, which will be essential for disease prevention. 

A living document

This review will almost certainly be part of an ongoing conversation. In the paper, the authors note: "This proposal represents a living document…" In other words, researchers continue to learn more about TDP-43 and how it becomes dysfunctional. For example, since TDP-43 pathology affects the splicing of many different proteins, current studies are focusing on potentially important upstream mechanisms that could influence TDP-43 activity.

In the larger picture, the authors hope this framework will inspire more creative approaches to recognize, treat and ultimately prevent neurodegenerative diseases.

"We need broad buy-in from the community to incorporate TAND into our thinking," said Dr. Benatar. "When we wrote this, we purposefully brought in clinicians who specialize in ALS, FTD, and LATE, as well as patient advocacy groups and representatives from biotechnology and the pharmaceutical industry. If we're going to change how the field thinks about these conditions, we need everyone involved."