Charcot disease: sleep disorders precede the appearance of the first motor symptoms

Charcot disease: sleep disorders precede the appearance of the first motor symptoms


MOTORS (marking by immunohistochemistry for cats) in the lumbar part of the spinal cord in murin models of SLA. 100 mm scale. © Simon J Guillot, Daniel Beckett and Matei BolboreaMOTORS (marking by immunohistochemistry for cats) in the lumbar part of the spinal cord in murin models of SLA. 100 mm scale. © Simon J Guillot, Daniel Beckett and Matei Bolborea

Amyotrophic lateral sclerosis (SLA), or Charcot disease, is a serious neurodegenerative disease which leads to a progressive paralysis of the muscles involved in voluntary motor skills. To date, no curative treatment exists for this disease whose outcome is fatal after 3 to 5 years of evolution on average. Researchers from Inserm and the University of Strasbourg, at the Research Center in Biomedicine, have just taken one more step in understanding the mechanisms in work in the disease. In a new study, they show that the characteristic symptoms of SLA are preceded by sleep alterations. Their work suggests that sleep disorders would be present before the appearance of motor impairment and respiratory problems. They reveal a new role of certain hypothalamus neurons in the occurrence of these sleep disorders associated with ALS. These works, published in the journal Science Translational Medicine, Identify in the brain new potential therapeutic targets and offer the exploration of a new family of molecules to counter the effects of lack of sleep.

Amyotrophic lateral sclerosis (SLA) is due to the progressive death of nerve cells called snowmobiler. This degeneration causes a progressive and rapid atrophy of the muscles, and leads to a loss of autonomy linked to the appearance of motor disorders and deficits. Most often, it is the achievement of the respiratory muscles that causes the death of patients.

The search effort for recent years has significantly developed knowledge on genetics and biology of this disease. On the other hand, it is still difficult to establish precisely the mechanisms which initiate and maintain the neuronal degeneration involved in the SLA. Unraveling the mystery of these mechanisms is one of the research objectives of the team from Luc Dupuis and Matei Bolborea, both inserm researchers at the Strasbourg biomedicine research center (Inserm/University of Strasbourg).

The progression of the disease reaches respiratory functions and therefore induced sleep disorders during its evolution. However, it was not determined if these disorders could preexist in motor symptoms, as observed in several neurodegenerative diseases (Parkinson or Alzheimer’s). When do they appear? Are they a consequence of the appearance of motor disorders and deficits? These questions were studied by the team of Luc Dupuis and Matei Bolborea, thanks to a close collaboration with the German Center for the Study of Neurodegenerative Diseases (DZNE) of ULM.

In their latest work, the researchers obtained and analyzed several dozen sleep records of groups of people with ALS, at different stages of the disease. Records that they have compared to control groups.

A first group was made up of patients with SLA at a stage where they had not yet developed respiratory symptoms. Another was made up of pre-symptomatic people, carrying certain genetic changes characteristic of the disease (these people had an increased risk of declaring the disease).

These tests indicate that the two groups of individuals suffered from the same type of sleep disorders: a greater awakening time and a deep amount of sleep lower than the data from control groups.

The results suggest that sleep disorders are present and observable, and this early, several years before the manifestation of motor disorders.

Restore sleep of patients with SLA

Following this discovery, the researchers tried to find the origin of these sleep disorders in the brain – they were interested in specific neurons found in the hypothalamus and known to play an important role in stimulating the ‘Awakening state: Orexine neurons[1]. On mouse models with ALS, the team has described the same types of sleep disorders. Scientists have also discovered that neurons circuits in which orexin neurons operate are altered by the disappearance of additional neurons during the disease.

They then had the idea of ​​administering an inhibitor molecule in Orexine, found in a sleeping pill already marketed and prescribed for insomnia[2]. Thanks to this treatment, they managed to restore sleep in animals by a single oral take. Restoration of the activity of annex neurons in orexin neurons enabled, after 15 days of treatment, a motioneuron conservation in mice.

A clinical trial is underway to test the molecule on patients with SLA. The objective is, ultimately, to test if a restored sleep can have an effect on the progression of the disease.

“Our study had the main ambition to try to reconstruct what is going on in patients before they were sick. These discoveries on the chronology of symptoms allow us to rethink the role of the brain and particularly that of the hypothalamus in the beginning of the pathology and to imagine new therapeutic targets ”, Explains Matei Bolborea, co-deeper author of the study.

«The discoveries of our team are important on two levels. First of all, they highlight a new chronology of SLA symptoms, again questioning the origins of the disease, and in particular the role of the brain in its genesis, Explains Luc Dupuis, co-deeper author of the study. They also represent a slight hope for the patients, and those who declare the disease, imagining that Idag on the first manifestations of it can slow down its extremely rapid progression. »»

[1]Studies reveal, for example, that narcoleptic people have less orexin neurons than others.

[2] It is the SUVOREXANT® which belongs to the class of drugs called hypnotics, whose marketing is authorized in the United States.

These contents could also interest you:

Related Articles