Comparing Differential Gene Expression in Chronic Traumatic Encephalopathy, Parkinson's Disease, and Bipolar Disorder

Abstract

Introduction. Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder that isdefined, neuropathologically, by the presence of aggregated hyperphosphorylated tau in the neurons andastrocytes of the perivascular area that is located deep in the cerebral sulci. The lesion is associated withrepetitive brain trauma, from the spectrum of asymptomatic subconcussive head injury to grossly identifiablefeatures of concussion. Although the diagnostic neuropathology of CTE is well-characterized, the precisemechanism that causes this to occur in CTE is not yet clearly elucidated. The features of hyperphosphorylatedtau in CTE is quite similar with Alzheimer’s Disease (AD), as is the reduced expression of certain genes thatare required to dephosphorylate tau, which is the putative culprit in the generation of amyloid aggregatesand hyperphosphorylated tau.1 In comparison, Parkinson’s Disease (PD) is a neurodegenerative disease thatis caused by accumulation of misfolded alpha-synuclein (α-syn) that causes the formation of intraneuronalLewy Body aggregates. The pattern of accumulation for α-syn involves the olfactory bulb and the gut withprogressive involvement of the posterior part of the brain.2 Despite establishing the presence of two differentintraneuronal inclusions for CTE and PD, contact sports associated with the clinical spectrum of CTE has beenshown to present with Parkinsonian features along with dementia. Mood disorders has been reported to occurin patients with these neurologic conditions. Several studies have documented that patients had a previousexperience of traumatic brain injury prior to the diagnosis of Bipolar Disorder (BD). A review of electronicliterature suggested that having an earlier diagnosis of BD increased the likelihood of having a diagnosis ofPD in the future.3,4 Objectives. This research aimed to compare the over- and underexpressed genes in cases with Parkinson'sDisease (PD), cases with Bipolar Disorder (BD), and cases with Chronic Traumatic Encephalopathy (CTE) versusnormal controls. This was done to determine if parallel overexpression in certain genes may indicate the possible association at the level of gene expression. Identifying similar RNA sequence establishing gene expression may provide an insight to the relationship of the diseases in terms of pathobiological behavior. Determining the similar over- or underexpression pattern may provide an insight on the common pathobiologic mechanisms that may be the reason for the three disorders being associated by way of pre-morbid or co-morbid condition. Methodology. Transcripts from the public domain archive of the NCBI SRA were identified for the RNA sequence (RNAseq) of interest using the search string “Chronic Traumatic Encephalopathy,” “Bipolar Disorder,” and “Parkinson.” Only public domain transcriptome files of post-mortem brain samples labeled as RNAseq dataextracted thru the Illumina platform that have a paired normal control were selected. A total of ten (10)cases for each disorder and thirty (30) normal subjects for control in the NCBI SRA RNAseq database witha whole exome sequence file that was available for public domain use was utilized for differential geneexpression analysis.6,7,8 Results and Discussion. Among 21,122 identified genes from the RNAseq, the analysis was able to identify26 genes exhibiting increased expression of up to >15 log2 fold change among cases with CTE, PD, andBD compared with normal controls. In contradistinction, only 6 well-described genes exhibited a decreasedexpression among cases with CTE and BD compared to normal controls. However, there were no identified genes that exhibited underexpression in cases with PD compared with normal controls. The identification of parallel gene overexpression among the CTE, BD, and PD groups with respect to structural integrity, cellular metabolism, homeostasis, and apoptosis may indicate a common pathway that have been initiated as part of the response to maintain tissue function or as a consequence of the underlying pathobiologic mechanism that caused the primary lesion.