ABSTRACT: Background: Parkinson's disease (PD) is characterized by its progression of motor-related symptoms such as tremors, rigidity, slowness of movement, and difficulty with walking and balance. Comorbid conditions in PD individuals include insulin resistance (IR) and narcolepsy-like sleep patterns. The intersecting sleep symptoms of both conditions include excessive daytime sleepiness, hallucinations, insomnia, and falling into REM sleep more quickly than an average person. Understanding of the biological basis and relationship of these comorbid disorders with PD may help with early detection and intervention strategies to improve quality of life. Methods: In this study, an integrative genomics and systems biology approach was used to analyze gene expression patterns associated with PD, IR, and narcolepsy in order to identify genes and pathways that may shed light on how these disorders are interrelated. A correlation analysis with known genes associated with these disorders (LRRK2, HLA-DQB1, and HCRT) was used to query microarray data corresponding to brain regions known to be involved in PD and narcolepsy. This includes the hypothalamus, dorsal thalamus, pons, and subcoeruleus nucleus. Risk factor genes for PD, IR, and narcolepsy were also incorporated into the analysis. Results: The PD and narcolepsy signaling networks are connected through insulin and immune system pathways. Important genes and pathways that link PD, narcolepsy, and IR are CACNA1C, CAMK1D, BHLHE41, HMGB1, and AGE-RAGE. Conclusions: We have identified the genetic signatures that link PD with its comorbid disorders, narcolepsy and insulin resistance, from the convergence and intersection of dopaminergic, insulin, and immune system related signaling pathways. These findings may aid in the design of early intervention strategies and treatment regimes for non-motor symptoms in PD patients as well as individuals with diabetes and narcolepsy.
