What if your nights revealed ALS years in advance?
Researchers at Inserm have taken a significant step forward in understanding Amyotrophic Lateral Sclerosis, also known as Charcot disease, offering hope for a new therapeutic strategy to slow its progression. Their work highlights the role of the hypothalamus and reveals that sleep disturbances may appear long before motor symptoms develop. Even more promising, a molecule that restored sleep in mice helped preserve motor neurons.
According to the French research team, sleep disorders precede the onset of motor symptoms in ALS. Could treating sleep disturbances help slow the disease? That is precisely what scientists observed in animal models.
To date, there is no cure for ALS, a neurodegenerative disease that typically leads to death within three to five years of symptom onset. ALS is characterized by the progressive death of nerve cells known as motor neurons. As these cells degenerate, patients experience rapid and progressive muscle atrophy, motor impairments, and loss of independence. Ultimately, damage to the respiratory muscles leads to death.
As with several other neurodegenerative conditions, researchers from Inserm and the University of Strasbourg wondered whether sleep disorders, often viewed as a consequence of disease progression, might actually precede motor decline. They also questioned whether restoring sleep could slow the disease’s course.
To explore this, the team analyzed dozens of sleep recordings from groups of people living with ALS at different stages. One group had not yet developed respiratory symptoms. Another carried genetic mutations that increased their risk of developing the disease. Their results were compared with control groups.
The hypothalamus involved in sleep disturbances
“These tests indicate that both groups of individuals experienced the same type of sleep disturbances: increased wakefulness and reduced deep sleep compared with control groups,” the authors explained in a statement released on February 4. The findings, published in Science Translational Medicine, suggest that sleep disorders are present and detectable several years before motor symptoms emerge.
The researchers then looked for the origin of these disturbances in the brain. Their focus turned to orexin neurons, specialized cells in the hypothalamus known to regulate wakefulness. In mouse models of ALS that exhibited similar sleep abnormalities, the team discovered that the neural circuits involving these orexin neurons were altered. Supporting neurons within these circuits had disappeared as the disease progressed.
A promising molecule to slow disease progression
The scientists administered an orexin inhibitor, a drug already prescribed to treat insomnia, to the affected mice. The results were striking. After a single oral dose, the mice’s sleep was restored. Activity in the supporting neurons connected to orexin neurons also improved. After 15 days of treatment, preservation of motor neurons was observed in the mice.
The research team now hopes to test this molecule in patients with ALS. Could restoring sleep slow the progression of the disease?
“Our team’s discoveries are important on two levels,” explained Luc Dupuis, co senior author of the study. “First, they highlight a new timeline of ALS symptoms, once again questioning the origins of the disease, particularly the role of the brain in its development. They also offer a glimmer of hope for patients and those who may develop the disease, by suggesting that acting on its earliest manifestations could slow its extremely rapid progression.”
Did you know?
ALS affects approximately 8,000 people in France, according to the Association for ALS Research. Its annual incidence is 2.7 cases per 100,000 inhabitants. It is a rare neurodegenerative disorder marked by the destruction of motor neurons, the cells responsible for voluntary movement.
The disease typically appears between ages 50 and 70. ALS is progressive and usually leads to death within three to five years after the first signs. In most cases, failure of the respiratory muscles is the cause of death. In about 30 percent of cases, the disease begins with difficulty speaking or swallowing. In others, it starts with weakness or discomfort in an arm, leg, or hand.
Disease progression may include:
• muscle cramps and stiffness in muscles and joints;
• muscle wasting and coordination problems affecting walking, grasping objects, swallowing, or speaking;
• at an advanced stage, respiratory muscles can no longer function adequately.
These findings suggest that sleep, often overlooked in neurodegenerative diseases, may hold a key to understanding and potentially slowing ALS.