When the putative phosphoamino acids were displayed in this model and the known structure, it is evident that Sso1p S23, S24 and S79 are located either in the Hb helix or at the unstructured amino-terminal peptide. At both locations, they are apparently accessible for cytosolic interactions. Deficiency in hypocretin peptides production or defects in their receptors were found to cause narcolepsy-like symptoms in animals. In humans, narcolepsy with cataplexy is characterised by selective loss of hypocretin neurons in the brain with low levels of hypocretin in the cerebro-spinal fluid. Further evidence has accumulated supporting the causal role of hypocretin deficiency in the origin of NC, Screening Libraries however, participation of hypocretin signaling in other forms of central hypersomnia including narcolepsy without cataplexy or idiopathic hypersomnia is less understood, although a partial hypocretin deficiency is possible in the former condition. Several studies failed to provide evidence for a humoral autoimmune response against the hypocretin peptides. However, transfer of total IgG autoantibodies from patients with NC to mice supported the presence of functional autoAbs which might be relevant to NC and positive effect of intravenous IgG to normalize CSF hypocretin-1 level has been reported in an NC patient. Failure to detect autoAbs response to the hypocretin peptides in NC might be related to the prevailing concept of autoAbs being the pure markers of autoimmune disease. However, another so far largely unexplored concept is to consider the presence of natural autoAbs reacting with self molecules including neuropeptides as a physiological phenomenon. Because any autoAbs exist as a free fraction and as immune complexes, it is possible that relative amount of free and complexed autoAbs against hypocretin peptides may participate in the regulation of hypocretin availability and therefore can be associated with sleep/wake dysregulation. To address this question, in the present study, serum levels of free and dissociated autoAbs reacting with hypocretin-1 peptide were measured in patients with central hypersomnias and compared to healthy subjects and to biological and clinical parameters relevant to sleep disorders. The present data revealed altered characteristics of hypocretin-1 reactive autoAbs in subjects with central hypersomnia. We found that levels of hypocretin-1 free IgG autoAbs were lower in NC, NWC and HI groups of patients than in controls. These data are in agreement with a previous report showing low levels of free hypocretin autoAbs in NC patients. Because a fraction of autoAbs exist in immune complexes which are not detectable in normal assays, we measured the levels of total autoAbs reactive with hypocretin-1 peptide using a NaCl-glycine buffer which dissociates immune complexes. With this approach, we found that in contrast to the free fraction of hypocretin-1 autoAbs, total IgG autoAbs are increased in the patients with NC. We acknowledge some limitation of this analysis since few values of total IgG autoAbs.