Scientists from KU Leuven and the VIB Center for Brain and Disease Research have identified an intriguing new lead in the biology of amyotrophic lateral sclerosis (ALS)—the role of specific mutations in primary cilia. They believe this could open a potential new avenue for therapeutic development.
Their study was published in Brain and the lead author is Mathias De Decker of the Department of Neurosciences, Laboratory of Neurobiology and Leuven Brain Institute.
ALS, also known as Lou Gehrig’s disease, is a devastating neurodegenerative disease that leads to the destruction of motor neurons and eventually death. The average life span after diagnosis of this incurable disease is two to five years. It is the most common degenerative motor neuron disease in adults and it’s estimated that 331,000 people worldwide have the condition. It is characterized by a selective loss of motor neurons, resulting in progressive muscle weakness and paralysis, as well as swallowing and speech difficulties.
The mechanisms of motor neuron death in ALS remain elusive, and there are currently no effective treatments to halt or reverse the progression of the disease. This team of researchers is pointing to the dysfunction of cilia, which are essential for receiving and processing vital signals.
Mutations in C21orf2 are known to disrupt cilia in other diseases. This prompted the team to investigate how these mechanisms play out in ALS.
The study, in collaboration with researchers from the lab of Ludo Van Den Bosch at VIB-KU Leuven, 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,” said De Decker. “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 signaling, and rescued neuromuscular junction formation. This discovery highlights primary cilia as a potential therapeutic target in ALS.
Strikingly, 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.
Philip Van Damme, senior author 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.”
