Analysis of the Phosphoproteome of Jnk1-/- vs Wild Type Mouse Brain Provides Novel Insight on JNK1's Interaction Profile and Its Connection to Various Mental Disorders
Hong, Ye (2018-03-05)
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c-Jun N-terminal kinases (JNKs) are multifunctional kinases that are involved in various diseases. The JNK pathway plays a major role in cell death in response to a variety of stimuli; it hence plays a part in diseases such as type-2 diabetes, cancer, stroke, heart disease, and inflammatory diseases. Human genetics studies have linked the JNK pathway to neurological disorders; however, the mechanisms are largely unknown. To understand more about how JNK1 related mechanisms connect to various mental disorders, entire phosphoproteome data sets over a lifetime were analyzed with bioinformatics methods in this study. The experiment consists of two genotypes of mice, Jnk1-/- (KO) and wild type (WT), each divided into 4 age groups representing key development stages. The protein molecules from the brain were extracted and purified, the identity and quantity of the proteins was analyzed by mass spectrometry and interpreted by MASCOT. The data quality was examined with R analysis; group patterns were explored with graphical analysis; differentially expressed entries were extracted by 4 different statistical methods; the extracted entries were uploaded into Metacore for enrichment analysis; the connections of the significant entries with various mental disorders were explored by overlap investigation of enriched pathways, as well as genes. The protein level interactions between important linking genes were explored by network building in Cytoscape. This revealed enrichment of genes for Huntington’s Disease as expected, but also for neuropsychiatric disorders, importantly, a high level of enrichment of signaling pathways was found providing potential mechanistic insight on the disease basis. Due to the limited number of biological repeats and the inherent biological and technical variance, the differential expression analysis methods did not yield satisfactory results. A new method could be developed. The large percentage of intensity increase of Jnk1-/- phosphoproteins compared to wild type was not anticipated; future studies could compare this result to short term JNK1 suppression data, and JNK1 and JNK2 double knockout data to analyze the regulation deviation between long term and short term suppression of JNK1, and between different knockout conditions.