Dr. Pedro Ervilha Pereira
 Shifting the Tail of TDP-43: Characterising a Novel Myopathy-causing TDP-43 Variant
(promotor Prof. Bart Dermaut)

Diseases that damage the brain and nerves become more common as people get older. Some well-known examples are Alzheimer’s disease, Parkinson’s disease, Frontotemporal dementia, and Amyotrophic lateral sclerosis.
One problem researchers face is that these diseases can look very different from one person to another, which makes it difficult to understand exactly what causes them.
Even though they differ, many of these diseases share one common feature: certain proteins inside nerve cells build up into clumps (called aggregates). These clumps can damage the cells. Different diseases can involve different proteins, but some proteins appear in several conditions.
One important protein is TDP‑43. Scientists first noticed clumps of this protein in the brain and spinal cord of people with ALS. Later, they also found it in people with Frontotemporal dementia and Alzheimer’s disease. Because of this, diseases involving abnormal TDP-43 are sometimes grouped together and called TDP-43 proteinopathies.
For a long time, scientists believed that TDP-43 mainly caused problems in nerve cells. However, more recent research has shown that clumps of TDP-43 can also appear in muscle tissue in people with ALS. This raises the possibility that these protein clumps might actually start forming in muscle.
Supporting this idea, TDP-43 problems have also been found in several muscle diseases, such as Sporadic inclusion body myositis, Oculopharyngeal muscular dystrophy, and Duchenne muscular dystrophy. This suggests that TDP-43 might directly play a role in muscle disease. Until now, however, scientists did not have clear genetic proof that a change in TDP-43 could directly cause a muscle disorder.

Why this myopathies behaves differently 

The genetic change affects a key part of the TDP-43 protein called the C-terminal region. This region normally helps the protein gather temporarily into structures called stress granules, which cells use to respond to stress.
Tests showed that the new variant forms protein clumps much faster than normal, even creating large, insoluble accumulations. Researchers call this behavior “super-aggregation.” This strong tendency to clump may explain why the protein builds up in muscle tissue. 
 

Effects on nerve cells 

Interestingly, when we tested this variant in the fruit fly Drosophila melanogaster, it did not harm nerve cells and did not shorten the flies’ lifespan. The protein also still worked normally in the experiments.
This suggests that the variant does not damage neurons, which is unusual for TDP-43 changes. 
 

What this discovery means 

Overall, this study describes a unique TDP-43 variant that:
Causes muscle disease rather than a brain disease
Forms protein clumps very easily (“super-aggregation”)
Does not appear toxic to nerve cells
This provides the first genetic evidence that TDP-43 can directly cause muscle disease. It also suggests that these protein clumps might sometimes protect nerve cells while harming muscle tissue. 
Because of this, the discovery could change how scientists think about TDP-43 diseases and possibly even conditions like ALS in the future.