Cellular mechanisms involved in induction of selective degeneration of orexin neurons in the hypothalamus

Abstract

Narcolepsy is a kind of sleep disorder featured by selective loss of orexin neurons in the lateral hypothalamus. Several lines of evidence, including association with specific HLA haplotypes, gene polymorphism in T cell receptor and detection of autoantibodies in a subpopulation of patients, suggest that autoimmune responses play an important role in the pathogenesis of this disorder. Potential relationship with influenza virus infection has also been a matter of interest. However, these events may not be able to explain all cases of narcolepsy. Based on the structural features of orexin, in addition to the findings on the characteristics of orexin neurons obtained from studies in organotypic hypothalamic slice cultures, we proposed novel mechanisms potentially involved in selective degeneration of orexin neurons. Increase in local production of nitric oxide induced by several life style-related conditions such as shortage of sleep and intake of high fat diet leads to inactivation of protein disulfide isomerase. Consequently, abnormal aggregates of orexin and/or its precursor that possess two intra-molecular disulfide bonds accumulate within orexin neurons. In addition to the increase in endoplasmic reticulum stress, accumulation of orexin as abnormal aggregates leads to increased excitability of orexin neurons by shutdown of feedback inhibition resulting from deficits in orexin release. These mechanisms may provide a clue to understand the pathogenic mechanisms of various neurological and psychiatric disorders accompanied by a decrease of orexin.