CE17 - Recherche translationnelle en santé

Narcolepsy type 1 physiopathology – NARCO-T1

Submission summary

Narcolepsy type 1 (NT1) is a disabling orphan disorder characterized by excessive daytime sleepiness and cataplexy, often associated with hypnagogic hallucinations, sleep paralysis, nighttime sleep disruption and weight gain. NT1 is a chronic disorder, and in the large majority of patients it is a sporadic disorder with the main peak of disease onset at 16 years of age.
We showed in 2000 that NT1 is due to the specific loss of hypocretin (orexin) neurons within the hypothalamus. Although the etiology of the disease, the reason why the hypocretin neurons die is still obscure, it is clear that both genetic and environmental factors are important. A main specific genetic susceptibility marker is known since more than 95% of patients carry the human leukocyte antigen DQB1*06:02 allele. Increasing evidence argue for an autoimmune pathogenesis with epidemiological studies underlying a strong association between H1N1 influenza virus vaccination and narcolepsy following the 2009 vaccination campaign.
The mechanisms underlying such association remain unclear and may involve either a specific immune response to H1N1 with potential molecular mimicry or a large non-specific stimulation of the immune system with increased brain inflammation/blood-brain permeability, allowing the autoimmune process to reach hypocretin neurons resulting in NT1.
Recently we have provided evidence supporting the autoimmune hypothesis. We have generated a mouse model in which an induced and targeted neuro-inflammation was able to kill specifically hypocretin neurons and provoke sleep fragmentation and cataplexy episodes, thus an autoimmune mouse model for NT1. We have also reported an immune signature in NT1, alteration in P2RY11 signaling, and revealed the release of several cytokines and growth factors in the sera of NT1 patients.
Now, our goal is to use a variety of complementary approaches to test realistic hypotheses regarding the immune mechanisms that could induce NT1. Our project is based on a translational approach using both human and animal models. Altogether preclinical and clinical research studies within this project have the objectives to decipher the autoimmune mechanisms able to destroy hypocretin-producing neurons and investigate how environmental factors such as infection or vaccination trigger an autoimmune response against CNS neurons. Our approaches include the in-depth study of cases of early-diagnosed NT1, induced or not by H1N1 vaccination, and the use of original animal models to test the different immunological pathways that could lead to NT1. The strong position of the 3 academic partners in the domain of sleep, sleep disorders and neuro-immunology, their real and efficient synergy and the access to the biobank of the French reference national center for narcolepsy in Montpellier are major advantages for the success of the project and will contribute to the scientific valorization of the results. New treatment strategies could emerge from the identification of the precise immunological alteration, especially early after disease onset when the potential immune process targeting hypocretin neurons is not too advanced and could be reverted. Our results may lead to new ways to treat such pathologies by opening up a new field of therapy potentially exploitable in public health politics, and leading to new patentable molecules.

Project coordination

Yves DAUVILLIERS (NEUROPSYCHIATRIE : RECHERCHE EPIDEMIOLOGIQUE ET CLINIQUE)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CRNL Centre de Recherche en Neurosciences de Lyon
CPTP CENTRE DE PHYSIOPATHOLOGIE DE TOULOUSE PURPAN
PSNREC NEUROPSYCHIATRIE : RECHERCHE EPIDEMIOLOGIQUE ET CLINIQUE

Help of the ANR 663,689 euros
Beginning and duration of the scientific project: March 2019 - 48 Months

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