Study Hones In On Primary Cilia Dysfunction in ALS

A study published today in Brain by researchers from KU Leuven and the VIB Center for Brain and Disease Research has uncovered a potential new direction in understanding Amyotrophic Lateral Sclerosis (ALS). The research focuses on primary cilia, microscopic antenna-like structures on cells that play a crucial role in signal reception and processing. 

The investigation stemmed from the 2016 identification of C21orf2 as an ALS-related gene by an international consortium led by Prof. Philip Van Damme. Mutations in this gene were known to affect cilia in other diseases, prompting researchers to explore its role in ALS.

The study revealed that C21orf2 mutations impair the formation and structure of primary cilia in motor neurons. Patients with these mutations exhibited fewer and shorter cilia, leading to disrupted signal transmission. Mathias De Decker, the study's first author, noted that this structural damage affects the sonic hedgehog (Shh) pathway, crucial for motor neuron health and neuromuscular junction formation.

Importantly, restoring C21orf2 levels in mutated cells repaired cilia defects, restored Shh signaling, and rescued neuromuscular junction formation. This finding suggests primary cilia could be a potential therapeutic target in ALS.

The research team also observed similar cilia defects in motor neurons from ALS patients with C9orf72 mutations, one of the most common genetic causes of ALS. This indicates that cilia dysfunction might be a broader issue in ALS biology, not limited to a single genetic subtype.

Prof. Van Damme commented, "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."