Novel genes associated with hypocretin-producing neurons identified by human gene expression profiling

Abstract

Narcolepsy type 1 is a sleep-wake disorder characterized by hypocretin deficiency. It has been considered an autoimmune disorder for decades due to the strong associating with the HLA-DQB1*06:02 allele and possible relations to the H1N1 pandemic in 2009. However, the pathophysiological mechanisms underlying the loss of hypocretin neurons is not understood. We hypothesize that a hypocretin neuron-specific antigen, other than hypocretin itself but sharing an expression pattern, may be the target of the autoimmune response leading to the development in individuals with narcolepsy type 1. In this study, we employed an in silico method to identify novel candidate antigens for an autoimmune response leading to the destruction of hypocretin cells. A combination of multiple publicly available datasets, based on human brain tissue from healthy individuals, was used to map the expression profile of hypocretin. Genes were categorized based on their expression pattern and its association with hypocretin expression. 15 candidate genes were identified as potentially relevant targets in the development of NT1, with varying degrees of confidence regarding the likelihood of their involvement. Six candidate genes also showed higher expression within hypocretin cells compared to other cells in the hypothalamus of which NPVF seems most promising. This study provides important new directions and potential targets for investigating and understanding the pathophysiology of narcolepsy type 1.