Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects motor neurons. The average life span after diagnosis of this incurable disease is two to five years. Now, researchers have identified a new lead: tiny, antenna-like structures 0n cells called primary cilia, which could open a potential new avenue for therapeutic development.
Despite extensive research, the mechanisms of motor neuron death remain elusive, and there are currently no effective treatments to halt or reverse the progression of the disease. Now, researchers are pointing to the dysfunction of cilia, microscopic antennas of cells, essential for receiving and processing vital signals.
In 2016, scientists identified C21orf2 as a new ALS-related gene. Mutations in C21orf2 were already known to disrupt cilia in other diseases. This prompted the team to investigate how these mechanisms play out in ALS.
The study revealed that mutations in C21orf2 impair the formation and structure of primary cilia. Motor neurons derived from patients with C21orf2 mutations had fewer cilia, and the cilia that remained were abnormally short.
“This structural damage prevents proper signal transmission,” says Dr. Mathias De Decker, first author.
“We saw that the sonic hedgehog (Shh) pathway—a key pathway for motor neuron health was disrupted. When this happens, motor neurons struggle to form essential connections between nerves and muscles, known as neuromuscular junctions.”
Further experiments showed that restoring C21orf2 levels in mutated cells repaired the cilia defects, restored Shh signalling, and rescued neuromuscular junction formation. This discovery highlights primary cilia as a potential therapeutic target in ALS.
The researchers also observed similar cilia defects in motor neurons from ALS patients with mutations in one of the most common genetic causes of ALS, C9orf72. This suggests that cilia dysfunction might not be limited to one genetic subtype but could represent a broader problem in ALS biology.
Professor Philip Van Damme said: “These observations raise many questions and open avenues for further research. Overexpression of C21orf2 could rescue the cilia defects and formation of neuromuscular junctions, suggesting that targeting primary cilia dysfunction could become a therapeutic strategy for ALS.”
