Narcolepsy: a neurodegenerative disease of the hypocretin/orexin system?

Narcolepsy is characterized by excessive daytime sleepiness (EDS), cataplexy, sleep paralysis and hypnogogic halluci-nations. Although the cause of narcolepsy has been unknown, two recent papers1.xA mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Peyron, C. et al. Nat Med. 2000; 6: 991–997CrossRef | PubMed | Scopus (1275)See all References, 2.xReduced number of hypocretin neurons in human narcolepsy. Thannickal, T. et al. Neuron. 2000; 27: 469–474Abstract | Full Text | Full Text PDF | PubMedSee all References represent the discovery of the century for this condition: narcolepsy is associated with a massive reduction in the number of hypocretin Hcrt/orexin cells. As highlighted in a recent TINS article3xThe hypocretin/orexin ligand–receptor system: implications for sleep and sleep disorders. Kilduff, T.S. and Peyron, C. Trends Neurosci. 2000; 23: 359–365Abstract | Full Text | Full Text PDF | PubMed | Scopus (331)See all References3, degeneration of his system would have a profound effect on pathways involved in sleep/wake regulation.In 1999, the single gene autosomal recessive defect in the narcoleptic dog model was mapped to a mutation in the Hcrt receptor 2. This finding, together with the striking ‘cataplexy-like‘ periods of behavioral arrest found in the Hcrt/orexin knockout mouse, indicated a link between the Hcrt/orexin system and sleep/wake systems. Peyron et al.1xA mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Peyron, C. et al. Nat Med. 2000; 6: 991–997CrossRef | PubMed | Scopus (1275)See all References1 now report mutation screening of 74 narcoleptic patients at the three currently known loci of this system (Hcrt, Hcrtr1, and Hcrtr2) and found one subject with a Leu to Arg substitution in the signal-peptide region of the Hcrt gene that results in impaired intracellular trafficking and processing of Hcrt – this patient is one of the most severely affected individuals with this disorder. They also showed that Hcrt mRNA was undetectable in the hypothalami, pons and cortex of most post mortem narcoleptic subjects. By contrast, the Thannickal et al. paper2xReduced number of hypocretin neurons in human narcolepsy. Thannickal, T. et al. Neuron. 2000; 27: 469–474Abstract | Full Text | Full Text PDF | PubMedSee all References2 focused exclusively on the neuropathology of 4 narcoleptic and 12 neurologically normal individuals. Using antigen retrieval techniques to study narcoleptic brains, they found an 85–95% reduction in the number of Hcrt-containing cells and no change in the number of melanin concentrating hormone cells, a peptide whose distribution is coextensive with Hcrt. As previously diagrammed (Box 1 in Ref. 3xThe hypocretin/orexin ligand–receptor system: implications for sleep and sleep disorders. Kilduff, T.S. and Peyron, C. Trends Neurosci. 2000; 23: 359–365Abstract | Full Text | Full Text PDF | PubMed | Scopus (331)See all ReferencesRef. 3) loss of the connections of the Hcrt neurons to the cholinergic cells of the basal forebrain and pons and to the brainstem monoaminergic groups (the major neuronal systems involved in sleep/wake regulation), would result in an imbalance that probably contributes to both the EDS and cataplexy of narcoleptic patients.An association of narcolepsy with particular human leukocyte antigen (HLA) haplotypes was found in the 1980s, suggesting a possible autoimmune etiology. Given the genetic association with the HLA system and the increased glial-fibrillary-acid protein staining in the narco-leptic hypothalamus2xReduced number of hypocretin neurons in human narcolepsy. Thannickal, T. et al. Neuron. 2000; 27: 469–474Abstract | Full Text | Full Text PDF | PubMedSee all References2, the autoimmune hypothesis will be the immediate focus of attention: does a response to a microbial infection inadvertently target an epitope on the Hcrt-containing cells? Or alternatively, is there an invading pathogen or an environmental toxin that targets the Hcrt-containing cells? However, another possibility must be excluded before narco-lepsy can be formally admitted to the exclusive club whose members include the diseases of Drs Alzheimer and Parkinson: that Hcrt cells are still there but, for some reason, are no longer expressing Hcrt mRNA or Hcrt protein. Identification of other markers for the Hcrt-containing cells will be essential to exclude this transcriptional dysregulation possibility.The good news for human narcoleptics is that they do not have the receptor mutation found in narcoleptic canines and, thus, the path to therapy is now clear – the acronym ‘HRT’ will be re-defined as ‘Hcrt replacement therapy’ in certain circles. This field has progressed from the first description of a novel neuropeptide system with unknown function (1998), to identification of the consequence of defects in this system in animal models (1999), to understanding the neuropathology of a human disease (2000) with breathtaking speed and, as such, is a wonderful example of how basic research can lead to an understanding of a human disease. Hopefully, new therapies will arrive just as rapidly.