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

Main Article Content

Francia Victoria De Los Reyes
Carina Villamayor


Introduction. Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder that is
defined, neuropathologically, by the presence of aggregated hyperphosphorylated tau in the neurons and
astrocytes of the perivascular area that is located deep in the cerebral sulci. The lesion is associated with
repetitive brain trauma, from the spectrum of asymptomatic subconcussive head injury to grossly identifiable
features of concussion. Although the diagnostic neuropathology of CTE is well-characterized, the precise
mechanism that causes this to occur in CTE is not yet clearly elucidated. The features of hyperphosphorylated
tau in CTE is quite similar with Alzheimer’s Disease (AD), as is the reduced expression of certain genes that
are required to dephosphorylate tau, which is the putative culprit in the generation of amyloid aggregates
and hyperphosphorylated tau.1 In comparison, Parkinson’s Disease (PD) is a neurodegenerative disease that
is caused by accumulation of misfolded alpha-synuclein (α-syn) that causes the formation of intraneuronal
Lewy Body aggregates. The pattern of accumulation for α-syn involves the olfactory bulb and the gut with
progressive involvement of the posterior part of the brain.2 Despite establishing the presence of two different
intraneuronal inclusions for CTE and PD, contact sports associated with the clinical spectrum of CTE has been
shown to present with Parkinsonian features along with dementia. Mood disorders has been reported to occur
in patients with these neurologic conditions. Several studies have documented that patients had a previous
experience of traumatic brain injury prior to the diagnosis of Bipolar Disorder (BD). A review of electronic
literature suggested that having an earlier diagnosis of BD increased the likelihood of having a diagnosis of
PD in the future.3,4

Objectives. This research aimed to compare the over- and underexpressed genes in cases with Parkinson's
Disease (PD), cases with Bipolar Disorder (BD), and cases with Chronic Traumatic Encephalopathy (CTE) versus
normal 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 data
extracted 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 with
a whole exome sequence file that was available for public domain use was utilized for differential gene
expression analysis.6,7,8

Results and Discussion. Among 21,122 identified genes from the RNAseq, the analysis was able to identify
26 genes exhibiting increased expression of up to >15 log2 fold change among cases with CTE, PD, and
BD compared with normal controls. In contradistinction, only 6 well-described genes exhibited a decreased
expression 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.

Article Details

How to Cite
De Los Reyes, F. V., & Villamayor, C. (2020). Comparing Differential Gene Expression in Chronic Traumatic Encephalopathy, Parkinson’s Disease, and Bipolar Disorder. Philippine Journal of Pathology, 5(1). Retrieved from
Original Articles
Author Biographies

Francia Victoria De Los Reyes, University of the East Ramon Magsaysay Memorial Medical Center, Quezon City

Graduate, AP/CP Residency Training Program, Department of Pathology and Pathology Laboratory 

Carina Villamayor, University of the East Ramon Magsaysay Memorial Medical Center, Quezon City

Chairperson, Department of Pathology


[1] Seo JS, Lee S, Shih JY, Hwang YJ et al. Transcriptome analyses of chronic traumatic encephalopathy show alterations in protein phosphatase expression associated with tauopathy. Experimental & Molecular Medicine. 2017; 49, e333. doi:10.1038/emm.2017.56
[2] Niu H, Shen L, Li T, Ren C, et al. Alpha-synuclein overexpression in the olfactory bulb initiates prodromal symptoms and pathology of Parkinson’s disease. Translational Neurodegeneration. 2018; 7:25.
[3] Drange OK, Vaaler AE, Morken G, Andreassen OA, et al. Clinical characteristics of patients with bipolar disorder and premorbid traumatic brain injury: a cross-sectional study. Int J Bipolar Disord. 2018; 6: 19. doi: 10.1186/s40345-018-0128-6
[4] Faustino PR, Duarte GS, Chendo I, et al. Risk of Developing Parkinson Disease in Bipolar Disorder: A Systematic Review and Meta-analysis. JAMA Neurol. 2020;77(2):192–198. doi:10.1001/jamaneurol.2019.3446
[5] Seng Zhu, Saïda Abounit, Carsten Korth, Chiara Zurzolo. Transfer of disrupted-in-schizophrenia 1 aggregates between neuronal-like cells occurs in tunnelling nanotubes and is promoted by dopamine. Open Biology, Royal Society, 2017, 7 (3), pp.160328. ⟨10.1098/rsob.160328⟩. ⟨pasteur-01515780⟩
[6] Homo sapiens (human) Transcriptome analyses of chronic traumatic encephalopathy show alterations in protein phosphatase expression associated with tauopathy. Accession: PRJEB13579.
[7] Homo sapiens (human) mRNA-Seq expression and MS3 proteomics profiling of human post-mortem BA9 brain tissue for Parkinson Disease and neurologically normal individuals. Accession: PRJNA283498.
[8] Homo sapiens (human) RNA-sequencing of the brain transcriptome implicates dysregulation of neuroplasticity, circadian rhythms, and GTPase binding in bipolar disorder. Accession: PRJNA231202.
[9] Galaxy. The Galaxy Project. 2020.
[10] European Nucleotide Archive. European Molecular Biology Laboratory-European Bioinformatics Institute. 2020.
[11] GRCh38. Genome Reference Consortium Human Build 38. Genome Reference Consortium
[12] Kim D, Langmead B, Salzberg S. HISAT: a fast spliced aligner with low memory requirements. Nature Methods. 2015, 12 (4), pp. 357–360. doi:10.1038/nmeth.3317
[13] Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features In Bioinformatics. 2013. 30 (7), pp. 923–930. doi:10.1093/bioinformatics/btt656
[14] Bjoern A. Gruening. Galaxy wrapper. 2014.
[15] RStudio. RStudio, PBC. 2020.
[16] The R Project for Statistical Computing. The R Foundation. 2020.
[17] Szklarczyk D, Gable AL, Lyon D, Junge A, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019 Jan; 47:D607-613
[18] Nakajima H, Koizumi K. Family with sequence similarity 107: A family of stress responsive small proteins with diverse functions in cancer and the nervous system (Review). Biomed Rep. 2014;2(3):321–325. doi:10.3892/br.2014.243
[19] Masana M, Westerholz S, Kretzschmar A, et al. Expression and glucocorticoid-dependent regulation of the stress-inducible protein DRR1 in the mouse adult brain. Brain Struct Funct. 2018;223(9):4039–4052. doi:10.1007/s00429-018-1737-7
[20] Jellinger, K., Paulus, W., Grundke-Iqbal, I. et al. Brain iron and ferritin in Parkinson's and Alzheimer's diseases. J Neural Transm Gen Sect 2, 327–340 (1990).
[21] Omar NN, Tash RF, Shoukry Y, El Saeed KO.Breaking the ritual metabolic cycle in order to save acetyl CoA: A potential role for mitochondrial humanin in T2 bladder cancer aggressiveness. J Egypt Natl Canc Inst. 2017 Jun;29(2):69-76. doi: 10.1016/j.jnci.2017.04.001. Epub 2017 Apr 24.
[22] Tarze A, Deniaud A, Le Bras M, Maillier E, et al. GAPDH, a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization. 2007 Apr 19;26(18):2606-20. Epub 2006 Oct 30.
[23] Zinkie S, Gentil BJ, Minotti S, Durham HD. Expression of the protein chaperone, clusterin, in spinal cord cells constitutively and following cellular stress, and upregulation by treatment with Hsp90 inhibitor. Cell Stress Chaperones. 2013;18(6):745–758. doi:10.1007/s12192-013-0427-x
[24] Zuehlke AD, Beebe K, Neckers L, Prince T. Regulation and function of the human HSP90AA1 gene. Gene. 2015;570(1):8–16. doi:10.1016/j.gene.2015.06.018
[25] Martinez-De Luna RI, Ku RY, Lyou Y, et al. Maturin is a novel protein required for differentiation during primary neurogenesis. Dev Biol. 2013 Dec 1;384(1):26-40. doi: 10.1016/j.ydbio.2013.09.028. Epub 2013 Oct 1.
[26] Schonkeren SL, Massen M, van der Horst R, Koch A, Vaes N, Melotte V. Nervous NDRGs: the N-myc downstream-regulated gene family in the central and peripheral nervous system. Neurogenetics. 2019;20(4):173–186. doi:10.1007/s10048-019-00587-0
[27] Zhang R, Zhu JC, Hu H, Lin QY, et al. MicroRNA-140-5p suppresses invasion and proliferation of glioma cells by targeting glutamate-ammonia ligase (GLUL). Neoplasma. 2020 Jan 27. pii: 190514N432. doi: 10.4149/neo_2020_190514N432. [Epub ahead of print]
[28] Wolf NI, van Spaendonk RML, Hobson GM, Kamholz J. PLP1 Disorders. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. 1999 Jun 15 [updated 2019 Dec 19].
[29] Barbarino JM, McGregor TL, Altman RB, Klein TE. PharmGKB summary: very important pharmacogene information for MT-RNR1. Pharmacogenet Genomics. 2016;26(12):558–567. doi:10.1097/FPC.0000000000000247
[30] Namer IJ, Steibel J, Poulet P, Armspach JP, et al.Blood-brain barrier breakdown in MBP-specific T cell induced experimental allergic encephalomyelitis. A quantitative in vivo MRI study. Brain. 1993 Feb;116 ( Pt 1):147-59.
[31] Becker, M., Kuhse, J. & Kirsch, J. Effects of two elongation factor 1A isoforms on the formation of gephyrin clusters at inhibitory synapses in hippocampal neurons. Histochem Cell Biol 140, 603–609 (2013).
[32] Choi SH, Aid S, Bosetti F. The distinct roles of cyclooxygenase-1 and -2 in neuroinflammation: implications for translational research. Trends Pharmacol Sci. 2009;30(4):174–181. doi:10.1016/
[33] Jiang T, Cadenas E. Astrocytic metabolic and inflammatory changes as a function of age. Aging Cell. 2014;13(6):1059–1067. doi:10.1111/acel.12268
[34] Meunier B, Fisher N, Ransac S, Mazat JP, et al. Respiratory complex III dysfunction in humans and the use of yeast as a model organism to study mitochondrial myopathy and associated diseases. Biochim Biophys Acta. 2013 Nov-Dec;1827(11-12):1346-61. doi: 10.1016/j.bbabio.2012.11.015. Epub 2012 Dec 5.
[35] Dautant A, Meier T, Hahn A, Tribouillard-Tanvier D, di Rago JP, Kucharczyk R. ATP Synthase Diseases of Mitochondrial Genetic Origin. Front Physiol. 2018;9:329. Published 2018 Apr 4. doi:10.3389/fphys.2018.00329
[36] Kato, Tadafumi. (2001). The other, forgotten genome: Mitochondrial DNA and mental disorders. Molecular psychiatry. 6. 625-33. 10.1038/
[37] Tristan C, Shahani N, Sedlak TW, Sawa A. The diverse functions of GAPDH: views from different subcellular compartments. Cell Signal. 2011;23(2):317–323. doi:10.1016/j.cellsig.2010.08.003
[38] Ivashchenko A, Berillo O, Pyrkova A, Niyazova R, Atambayeva S. MiR-3960 binding sites with mRNA of human genes. Bioinformation. 2014;10(7):423–427. Published 2014 Jul 22. doi:10.6026/97320630010423
[39] Shen X, Li J, Liao W, et al. microRNA-149 targets caspase-2 in glioma progression. Oncotarget. 2016;7(18):26388–26399. doi:10.18632/oncotarget.8506
[40] Jia J, Zheng X, Hu G, et al. Regulation of pluripotency and self- renewal of ESCs through epigenetic-threshold modulation and mRNA pruning. Cell. 2012;151(3):576–589. doi:10.1016/j.cell.2012.09.023
[41] Deane CAS, Brown IR. Differential Targeting of Hsp70 Heat Shock Proteins HSPA6 and HSPA1A with Components of a Protein Disaggregation/Refolding Machine in Differentiated Human Neuronal Cells following Thermal Stress. Front Neurosci. 2017;11:227. Published 2017 Apr 24. doi:10.3389/fnins.2017.00227
[42] Garcia JM, Stillings SA, Leclerc JL, et al. Role of Interleukin-10 in Acute Brain Injuries. Front Neurol. 2017;8:244. Published 2017 Jun 12. doi:10.3389/fneur.2017.00244
[43] Musa J, Aynaud MM, Mirabeau O, Delattre O, Grünewald TG. MYBL2 (B-Myb): a central regulator of cell proliferation, cell survival and differentiation involved in tumorigenesis. Cell Death Dis. 2017;8(6):e2895. Published 2017 Jun 22. doi:10.1038/cddis.2017.244
[44] Daglas M, Adlard PA. The Involvement of Iron in Traumatic Brain Injury and Neurodegenerative Disease. Front Neurosci. 2018;12:981. Published 2018 Dec 20. doi:10.3389/fnins.2018.00981
[45] Lobo-Silva, D., Carriche, G.M., Castro, A.G. et al. Balancing the immune response in the brain: IL-10 and its regulation. J Neuroinflammation 13, 297 (2016).
[46] Kinzenbaw DA, Chu Y, Pena Silva RA, Didion SP, Faraci FM. Interleukin-10 protects against aging-induced endothelial dysfunction. Physiol Rep (2013) 1(6):e00149.10.1002/phy2.149
[47] Grilli M, Barbieri I, Basudev H, Brusa R, Casati C, Lozza G, et al. Interleukin-10 modulates neuronal threshold of vulnerability to ischaemic damage. Eur J Neurosci (2000) 12(7):2265–72.10.1046/j.1460-9568.2000.00090.x
[48] Barbosa IG, Bauer ME, Machado-Vieira R, Teixeira AL. Cytokines in bipolar disorder: paving the way for neuroprogression. Neural Plast. 2014;2014:360481. doi:10.1155/2014/360481
[49] Zhang K, Fu G, Pan G, et al. Demethylzeylasteral inhibits glioma growth by regulating the miR-30e-5p/MYBL2 axis. Cell Death Dis. 2018;9(10):1035. Published 2018 Oct 10. doi:10.1038/s41419-018-1086-8