Waking Up Narcolepsy and Brain Autoimmunity

Narcolepsy has fascinated scientists for centuries, as it a unique disease where reality and REM/dreaming sleep get confused with each other. Patients experience sleepiness, vivid dreaming bordering on hallucinations, sleep paralysis and cataplexy (muscle weakness triggered by emotions). Type 1 narcolepsy affects 0.03% of the population, and most often starts in children or adolescent. When I started to work on narcolepsy in 1987, nothing was known, and it was considered exceptionally rare. Thinking that finding the cause of the disease could reveal new sleep mechanisms and that the field was without competitors, I plunged myself in this topic of research. Working with a dog model of narcolepsy that transmitted the disorder as a single autosomal gene, we positionally cloned mutations in two dog breeds in 1999, at a time the dog genome was a no men land. The study revealed mutations in a G-Protein coupled receptor called hypocretin/orexin receptor 2, a receptor for a recently discovered peptide believed to be involved in appetite (thus the misnomer “orexin”). Since then, this system has become a major target for hypnotics (blockers), and a promising new treatment of narcolepsy itself (agonists under human clinical trial)is emerging. Remarkably, patient with narcolepsy who don’t have hypocretin are hypersensitive to these drugs, so that smaller dose than in normal individuals have disease reversing effects.

In parallel with this work, after finding that the hypocretin/orexin pathway was involved in canine narcolepsy, we discovered that in humans, the disease is not due to mutations of the receptor, but rather the result of an autoimmune disease destroying the 20,000 neurons containing hypocretin, not unlike type 1 diabetes and insulin. More studies have shown that this process is the result of T cell molecular mimicry between hypocretin itself and specific flu epitopes, with no involvement of antibodies as far as we know. This explains seasonal onset in the spring, and in a unique instance, post vaccination cases following a specific swine flu vaccine called Pandemrix. These discoveries are also opening a new field, that of CNS autoimmune mediated disorders. Indeed, many new brain diseases such as anti NMDAR, anti-LGi1, anti-GAD, anti-CASPR2 diseases are increasingly recognized and found to be amendable to immunotherapy. This field is also exploding although mechanisms behind CNS-specific immunity remain poorly understood. Autoimmunity seems to also play a role in neurodegenerative disorders such as Parkinson’s disease and Alzheimer dementia. CNS immune therapies have a bright future considering the rapid progress of immunotherapy in cancer. My research is described at mignotlab.com.