Tiny Cell Antenna Offer New Insights Into ALS

ALS, or amyotrophic lateral sclerosis, is a devastating neurodegenerative disease that affects motor neurons. After diagnosis, patients have an average life expectancy of two to five years, and there is currently no cure to stop the disease. Scientists from KU Leuven and the VIB Center for Brain Research have now made a remarkable discovery: small, antenna-like structures on cells, the so-called cilia, appear to play a key role in ALS. Their study, published in the scientific journal Brain, may open up new avenues for therapies.

ALS is the most common motor neuron disease in adults. The disease specifically affects motor nerve cells. These are the cells that send signals from the brain to the muscles to enable movement. In ALS, these cells are slowly lost, causing patients to gradually lose muscle strength. The consequences are severe: paralysis, difficulty swallowing, and difficulty speaking and breathing. Patients usually die within two to five years of the onset of symptoms.

Despite intensive research, the exact cause of motor neuron death remains unclear. Now scientists point to a possible link with the so-called cilia – microscopic 'antennas' on our cells that are essential for receiving and processing important signals.

A kink in the cable

In 2016, an international consortium, led in Belgium by Prof. Philip Van Damme, a neurologist at UZ Leuven and researcher at KU Leuven, identified the gene C21orf2 as a new ALS-related gene. Previous research had already shown that mutations in C21orf2 can damage cilia in other diseases. This gave the researchers the idea to investigate whether the same mechanism also plays a role in ALS.

In collaboration with the lab of Prof. Ludo Van Den Bosch (VIB-KU Leuven), the researchers discovered that mutations in C21orf2 disrupt the formation and structure of primary cilia. Nerve cells from ALS patients with these mutations had fewer cilia, and the cilia that were still present were noticeably shorter.

“These damages cause the cilia to stop working properly,” explains Mathias De Decker, first author of the study. “We saw that an important signaling pathway – the sonic hedgehog (Shh) signaling pathway – was disrupted. This pathway is crucial for the health of motor neurons. Without this pathway, neurons cannot make good connections with muscles, the so-called neuromuscular junctions. And without these connections, the muscles no longer function.”

Repairing the antenna

The researchers wanted to see if they could fix these problems. They did additional experiments and found that restoring the amount of C21orf2 in the damaged cells returned the cilia to normal. This reactivated the Shh signaling pathway, and allowed the nerve cells to reconnect to the muscles.

One notable observation: Similar cilia problems were also found in motor neurons from ALS patients with mutations in C9orf72 , one of the most common genetic causes of ALS. This suggests that cilia malfunctions are not limited to one subtype of ALS, but may play a broader role in the disease.

Prof. Philip Van Damme sees potential in these findings:

“These observations raise many questions, but also open new avenues of research. Restoring C21orf2 could repair the cilia problems and the connections to the muscles. This suggests that targeting cilia malfunctions could become a potential new therapeutic approach for ALS.”

Reference: De Decker M, Zelina P, Moens TG, et al. C21ORF2 mutations point towards primary cilia dysfunction in amyotrophic lateral sclerosis. Brain. 2024. doi: 10.1093/brain/awae331

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