A team of researchers led by Philip Van Damme and Ludo Van Den Bosch (VIB-KU Leuven Center for Brain & Disease Research) used stem cells derived from ALS-patients to study the role of TDP-43 mutations in the disease process. Interestingly, they found ways to reverse the symptoms in these cellular models, opening interesting new therapeutic avenues.  

Amyotrophic lateral sclerosis (ALS) is a deadly and currently incurable neurodegenerative disorder. The motor neurons controlling the body’s muscles gradually die off, resulting in increasing weakness, muscle wasting and eventually paralysis and death.

Some rare forms of ALS are caused by mutations in the gene encoding TDP-43, but nearly all ALS patients show cellular inclusions containing the TDP-43 protein, indicating that somehow, this protein plays an important role in the disease process. 

Patient cells in the lab
Prof. Philip Van Damme (VIB-KU Leuven-UZ Leuven) combines ALS patient care with research into the disease. In a new study conducted in collaboration with his colleague prof. Ludo Van Den Bosch (VIB-KU Leuven), Van Damme and his team investigate TDP‐43 protein behavior in motor neurons derived from stem cells obtained from three ALS patients with different TDP-43 mutations.

Van Damme: “To understand the basic disease mechanisms caused by mutations in the gene encoding TDP-43, we took skin biopsies from ALS patient and reprogrammed these dermal cells to stem cells, which were then differentiated to motor neurons. In this way, we can model what happens in this particular neuronal cell type in the patients.”

The researchers found that the mutations change the protein’s behavior in several ways. “TDP-43 is mislocalized, its processing is altered and it accumulates more readily,” says Raheem Fazal, PhD student in Van Damme’s team. “What’s more, its interactions with other proteins are affected, as is the transport of cellular organelles called mitochondria, important for energy production within the cells of our body.” 

Reversing cellular symptoms
“We saw the early signs of what we would expect based on what we actually see happening in ALS patients,” adds Van Damme. “Of course we wanted to see if we could do anything to mitigate these issues in the cells.”

The researchers used two techniques: they corrected the mutation in the TDP-43 gene using CRISPR/Cas9 and they treated the cells with a selective HDAC6 inhibitor—a compound which has previously been tested successfully in preclinical models of other neurodegenerative diseases related to protein aggregation, such as Charcot-Marie-Tooth disease.

“We found that both the pathological hallmarks and the transport defects could be rescued by genetic correction of the mutation or by treatment with the inhibitor,” says Van Damme.

“Our data show that HDAC6 inhibition can counteract the early stages of TDP‐43 pathology,” says co-lead author Ludo Van Den Bosch. ”If we can develop ways to deliver HDAC6 inhibitors to the brain in patients, we believe they could be a promising therapeutic option for TDP‐43-related diseases.”


HDAC6 inhibition restores TDP‐43 pathology and axonal transport defects in human motor neurons with TARDBP mutations, Fazal et al. EMBO J 2021

Questions from patients
A breakthrough in research is not the same as a breakthrough in medicine. The realizations of VIB researchers can form the basis of new therapies, but the development path still takes years. This can raise a lot of questions. That is why we ask you to please refer questions in your report or article to the email address that VIB makes available for this purpose: patienteninfo@vib.be. Everyone can submit questions concerning this and other medically-oriented research directly to VIB via this address.

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