[Hypocretins/orexins and narcolepsy: from molecules to disease]

In order to foresee a curative treatment for narcolepsy, it is crucial to determine whether or not human narcolepsy is a neurodegenerative disorder, as we suggested, and to understand the mechanisms involved. The current hypothesis regarding the etiology of human narcolepsy is that it is an autoimmune disorder, because of its strong association with the human leukocyte antigen (HLA DQB1*0602), with the Hcrt neurons as the target. This hypothesis is supported by our results (Peyron et al., 2000) and others (Thannickal et al., 2000) showing that Hcrt messengers RNA and mature peptides are absent or greatly reduced in the brain of HLA DQB1*0602 positive narcoleptic patients examined to date. It is of great importance to determine whether the absence of Hcrt is due to a neurodegenerative process or to a default in the transcription process. After a brief review on hypocretins and narcolepsy, we discuss on how to tackle the issue.