Sonic Hedgehog Protein Pathway May Be Compromised in ALS, Researchers Find

A signaling pathway involving a protein called sonic hedgehog (Shh) was found to be compromised in amyloid lateral sclerosis (ALS) patients in a study published in PLOS One.

Although the biological significance of this finding is not clear, this is the first time a study evaluated the role of Shh in ALS patients. A better understanding of the role of sonic hedgehog in ALS may not only help scientists better understand the disease, but could also help in the development of new therapies in the future.

Shh is a protein that plays a crucial role during the development of the nervous system. It continues to be essential in the adult brain, where it contributes to cell division and differentiation, maintains the integrity of the blood-brain barrier, and protects brain cells from stress caused by oxidative agents and excessive neuronal firing, all processes that are affected in ALS.

ALS is characterized by the loss of motor neurons, or cells of the nervous system that control the movement of muscles. Scientists don’t yet fully understand the exact mechanism of ALS disease onset. 

A team of researchers led by Dr. John Turnbull of the Department of Medicine, Division of Neurology, at McMaster University in Canada hypothesized that Shh signaling might play an important role in ALS.

In order to test their theory, the researchers measured protein and biological activity levels of sonic hedgehog in the fluid surrounding the brain and spinal cord (the cerebrospinal fluid) in ALS patients and healthy controls (people without ALS). They then tested whether these levels correlated with the severity and progression of the disease.

They analyzed levels of Shh in nine ALS patients, 12 patients with another neurological condition, and 13 healthy people who were undergoing spinal anesthesia for hip or knee replacement.

The results, published in a report titled “Cerebrospinal fluid from patients with amyotrophic lateral sclerosis inhibits sonic hedgehog function,” showed that there was no difference in the levels of Shh protein in ALS patients and healthy controls.

However when the researchers treated the cerebrospinal fluid obtained from ALS patients and controls with molecules that induce Shh activity, they saw increased activity in the cerebrospinal fluid of healthy controls as expected, but not in those of ALS patients. They concluded that the cerebrospinal fluid of ALS patients must contain a molecule that inhibits sonic hedgehog signaling.

The inhibitory effect in the cerebrospinal fluid of ALS patients did not correlate with ALS disease severity. However, the levels of cell signaling proteins, called IL-1β and TNF-α, did.

According to this, IL-1β and TNF-α levels were elevated in the cerebrospinal fluid of ALS patients, and the higher the levels were, the quicker the disease developed. Interestingly, TNF-α significantly inhibited the activity of Shh in vitro, suggesting a potential new role of TNF-α and Shh in the development of ALS.

 “A greater understanding of the common terminal pathway for motor neuronal dysfunction in ALS might lead to successful interventions, irrespective of more proximate causes,” Turnbull said in a news release highlighting the study, written by Heather Wood and published in the Nature Reviews Neurology.