Amyotrophic lateral sclerosis (ALS) is a serious and usually fatal neurodegenerative disorder in which motor neurons deteriorate and die. The disease causes a loss of movement that eventually affects a patient's ability to speak, eat, and breathe. ALS is due to known genetic factors in around ten percent of cases, and the physiological mechanisms underlying the disease are still not well understood. But scientists are making some progress.
In a new study reported in the journal Brain, researches have identified defects in a part of cells known as cilia, in ALS patients. Most cells in the body have a cilium, which can be thought of as a kind of signaling antenna that can sense and respond to various conditions. Defects in cilia are known to cause a wide range of diseases, depending on which cells carry those ciliary defects. These diseases are known collectively as ciliopathies.
In this work, the researchers identified genetic mutations in a gene called C21orf2, which are known to disrupt cilia. The researchers obtained cells from ALS patients, and used them to culture neurons. These neurons, which carried C21orf2 mutations, had fewer cilia, and the cilia they did have were abnormally short. Signals are not transmitted as they should be through these cilia, the investigators determined.
Ciliary defects have previously been shown to interfere with a signaling pathway known as sonic hedgehog (Shh); this was also a problem for neurons with C21orf12 mutations. The Shh pathway is important to the maintenance of motor neurons. The disruption of Shh impaired the formation of neuromuscular junctions, which are crucial links between nerves and muscles, explained first study author Dr. Mathias De Decker.
Additional work showed that when mutated cells were supplied with normal C21orf12, cilia defects were corrected, Shh signaling returned to normal, and neuromuscular junctions began to form again. Thus, cilia may present a therapeutic target for ALS.
Mutations in a gene called C9orf72 are known to be a genetic cause of ALS. The researchers also found that neurons with C9orf72 mutations carry similar cilia defects, which could indicate that ciliary dysfunction is a common mechanism underlying ALS.
"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," suggested senior study author Professor Philip Van Damme of the KU Leuven, among other appointments.
Sources: VIB (the Flanders Institute for Biotechnology), Brain
