The paradigm shift argues that shared protein pathology in the nucleus and cytoplasm should drive therapeutic drug development and clinical trials.
Redefining Neurodegeneration Through a Shared Biological Lens
On the surface, amyotrophic lateral sclerosis, frontotemporal dementia, and limbic-predominant age-related TDP-43 encephalopathy appear entirely distinct. ALS destroys motor neurons and leads to paralysis, FTD disrupts the frontal and temporal lobes to alter language and behavior, and LATE presents as a slowly progressing memory disorder mimicking Alzheimer’s disease in older adults. Yet beneath these distinct clinical phenotypes lies a common biological foundation governed by a single protein.
That realization has prompted a large international group of clinicians and researchers to publish a paradigm-shifting review in JAMA Neurology. Titled TDP-43-Associated Neurodegenerative Disease Conceptualization and Integrated Staging
and published on August 24, the paper coins the umbrella term TDP-43 associated neurodegenerative disease, or TAND, to link these conditions. The initiative is led by Michael Benatar, who serves as 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.
Historically, medicine has classified these conditions strictly by their outward symptoms. The new framework argues that phenotypical expressions are merely manifestations of an underlying biological dysfunction, urging researchers to shift their focus accordingly.
The Cellular Breakdown of TDP-43 Quality Control
To understand why these diverse conditions belong together, researchers point to the core biological function of TDP-43. Under normal cellular conditions, the protein oversees RNA splicing, a ubiquitous mechanism that allows a single gene to construct multiple distinct protein variants. When TDP-43 regulates this process correctly, it prevents errors in protein production.
In ALS, LATE, and roughly half of all FTD cases, however, that regulatory machinery breaks down. Instead of residing in the cell nucleus where it can perform RNA splicing, TDP-43 mislocalizes and accumulates within the cell’s cytoplasm.
“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.”
This dual failure—absence from the nucleus combined with cytoplasmic accumulation—drives aberrant RNA splicing. As a result, cells churn out abnormal forms and quantities of proteins, triggering the cellular proteostatic collapse characteristic of neurodegenerative proteinopathies.
Restructuring Drug Discovery and Clinical Trials
Viewing these conditions through the unifying concept of TAND carries immediate implications for biopharmaceutical development. Rather than treating each disease as an isolated target, developers can design therapies that address the underlying protein pathology across multiple conditions simultaneously.
This holistic approach could streamline drug pipelines and offer new hope for ultra-rare conditions like multisystem proteinopathy, where patients currently face a complete lack of therapeutic options. Furthermore, the framework aims to refine clinical trial design. FTD patients, for example, can present with either TDP-43 dysfunction or tau protein accumulation. While individuals with FTD-TDP-43 would theoretically benefit from a targeted treatment, patients with FTD-tau would not respond, making biological stratification essential for successful trials.
Broader Challenges in Proteostasis Research
While targeting protein misfolding opens new therapeutic avenues, the broader field faces persistent hurdles in translating preclinical discoveries into clinical treatments. Drug discovery remains complicated by the dynamic nature of protein species and lingering uncertainty over whether monomers, oligomers, or insoluble aggregates are primarily responsible for cellular toxicity.
Researchers also continue to grapple with incomplete knowledge of druggable targets and a general lack of validated biomarkers to monitor disease progression. Addressing these challenges will require collaborative ecosystems uniting patients, clinicians, basic researchers, and regulatory agencies to accelerate the creation of interventions designed to prevent, reverse, or delay neurodegenerative proteinopathies.
