Identification of Distinct and Common Biological Pathways in Neurodegenerative Diseases Using Correlation-based Gene Expression Analysis

Kübra Temiz; Esra Göv

doi:10.5281/zenodo.15655790

Authors

Kübra Temiz Bartın University https://orcid.org/0000-0002-3660-3204
Esra Göv Adana Alparslan Türkeş Science and Technology University https://orcid.org/0000-0002-5256-4778

DOI:

https://doi.org/10.5281/zenodo.15655790

Keywords:

Biological pathways, Gene expression, Neurodegenerative diseases, Transcriptome

Abstract

Neurodegenerative diseases (NDDs) are a group of diseases with devastating effects on the brain and nervous system that are often progressive and incurable. Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) are the most common diseases in this grou In this study, we sought to identify both common and disease-specific biological signaling pathways in AD, PD and ALS. Differential gene expression (DEGs) analyses were performed using microarray and RNA-Seq data from the NCBI GEO database, and specific gene co-expression networks were generated for each disease. These networks revealed differences in gene expression between diseased and healthy groups. Functional enrichment analyses were performed using the KEGG and Reactome databases, and the results showed that common biological pathways such as PI3K/Akt, calcium signaling, synaptic transmission, and transcriptional regulation were prominent. In addition, distinct biological pathways were also identified for each disease. These results contribute to a better understanding of the molecular structure of NDDs and provide potential biomarkers and therapeutic targets.

Author Biographies

Kübra Temiz, Bartın University

¹Department of Bioengineering, Faculty of Engineering, Adana Alparslan Türkeş Science and Technology University, 01250, Adana, Türkiye,

²Department of Biotechnology, Faculty of Science, Bartin University, 74100 Bartın, Türkiye

Esra Göv, Adana Alparslan Türkeş Science and Technology University

¹Department of Bioengineering, Faculty of Engineering, Adana Alparslan Türkeş Science and Technology University, 01250, Adana, Türkiye,

References

Katsnelson, A., De Strooper, B., and Zoghbi, H. Y., Neurodegeneration: From cellular concepts to clinical applications. Sci. Transl. Med. 8 (364) 364-382 (2016).

Tomruk, C., The four horsemen of neurodegenerative diseases Alzheimer, Parkinson, Huntington and amyotrophic lateral skleroz; clinical definition and experimental models. Istanb. Bilim Univ. Florence Nightingale J. Med. 4 (1), 37–43 (2018).

Dai, C.-Q., Luo, T.-T., Luo, S.-C., Wang, J.-Q., Wang, S.-M., Bai, Y.-H., Yang, Y.-L., and Wang, Y.-Y., p53 and mitochondrial dysfunction: novel insight of neurodegenerative diseases. Journal of Bioenergetics and Biomembranes 48, 337–347 (2016).

Zhang, W., Xiao, D., Mao, Q., and Xia, H., Role of neuroinflammation in neurodegeneration development. Signal Transduct. Target. Ther. 8 (1), 1–32 (2023).

Kujawska, M., Domanskyi, A., and Kreiner, G., Editorial: Common Pathways Linking Neurodegenerative Diseases—The Role of Inflammation. Front. Cell. Neurosci. 15, 754051 (2021).

Gan, L., Cookson, M. R., Petrucelli, L., and La Spada, A. R., Converging pathways in neurodegeneration, from genetics to mechanisms. Nat. Neurosci. 21 (10), 1300–1309 (2018).

Knopman, D. S., Amieva, H., Petersen, R. C., Chételat, G., Holtzman, D. M., Hyman, B. T., Nixon, R. A., and Jones, D. T., Alzheimer disease. Nature Reviews Disease Primers 7 (1), 33 (2021).

Poewe, W., Seppi, K., Tanner, C. M., Halliday, G. M., Brundin, P., Volkmann, J., Schrag, A. E., and Lang, A. E., Parkinson disease. Nature Reviews Disease Primers 3, 17013 (2017).

Masrori, J., Beckers, J., Gossye, H., and Van Damme, L., The role of inflammation in neurodegeneration: novel insights into the role of the immune system in C9orf72 HRE-mediated ALS/FTD. Mol. Neurodegener. 17 (1), 22 (2022).

Cantone, M. and Sacco, L., Editorial: Highlights in Alzheimer’s and Parkinson’s disease. Front. Hum. Neurosci. 17 (2023).

Wilson, D. M., Cookson, M. R., Van Den Bosch, L., Zetterberg, H., Holtzman, D. M., and Dewachter, I., Hallmarks of neurodegenerative diseases. Cell 186 (4), 693–714 (2023).

Amartumur, S., Nguyen, H., Huynh, T., et al., Neuropathogenesis-on-chips for neurodegenerative diseases. Nature Communications 15, 2219 (2024).

Singh, A. J., Ramsey, S. A., Filtz, T. M., and Kioussi, C., Differential gene regulatory networks in development and disease. Cell. Mol. Life Sci. 75 (6), 1013–1025 (2018).

Gov, E. and Arga, K. Y., Differential co-expression analysis reveals a novel prognostic gene module in ovarian cancer. Sci. Rep. 7 (1), 4996 (2017).

Kim, B., Choi, Y., Kim, H.-S., and Im, H.-I., Methyl-CpG Binding Protein 2 in Alzheimer Dementia. Int. Neurourol. J. 23(Suppl 2), S72-81 (2019).

Lee, S., Kim, T. K., Choi, J. E., Choi, Y., You, M., Ryu, J., et al., Dysfunction of striatal MeCP2 is associated with cognitive decline in a mouse model of Alzheimer's disease. Theranostics 12 (3), 1404–1418 (2022).

Ugbode, C., Hu, Y., Whalley, B., Peers, C., Rattray, M., and Dallas, M. L., Astrocytic transporters in Alzheimer’s disease. Biochem. J. 474 (3), 333–355 (2017).

Kori, M., Aydın, B., Unal, S., Arga, K. Y., Kazan, D., Metabolic biomarkers and neurodegeneration: A pathway enrichment analysis of Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. OMICS 20 (11), 645–661 (2016).

Huang, Y., Sun, L., Zhu, S., Xu, L., Liu, S., Yuan, C., Guo, Y., Wang, X., Neuroprotection against Parkinson's disease through the activation of Akt/GSK3β signaling pathway by Tovophyllin A. Frontiers in Neuroscience 14, 723 (2020).

Jha, S. K., Jha, N. K., Kar, R., Ambasta, R. K., and Kumar, P., p38 MAPK and PI3K/AKT Signalling Cascades in Parkinson’s Disease. Int. J. Mol. Cell. Med. 4 (2), 67–86 (2015).

Chapman, M. A. and Sorg, B. A., A Systematic Review of Extracellular Matrix-Related Alterations in Parkinson’s Disease. Brain Sci. 14 (6) (2024).

Melrose, J., Hayes, A. J., and Bix, G., The CNS/PNS Extracellular Matrix Provides Instructive Guidance Cues to Neural Cells and Neuroregulatory Proteins in Neural Development and Repair. Int. J. Mol. Sci. 22 (11), 5583 (2021).

Liu, Z., Yao, X., Yan, G., Xu, Y., Yan, J., Zou, W., Wang, G., Mediator MED23 cooperates with RUNX2 to drive osteoblast differentiation and bone development. Nature Communications 7, 11149 (2016).

Lee, H.-J., Bazinet, R. P., Rapoport, S. I., and Bhattacharjee, A. K., Brain Arachidonic Acid Cascade Enzymes are Upregulated in a Rat Model of Unilateral Parkinson Disease. Neurochem. Res. 35 (4), 613–619 (2010).

Kovacs, M., Alamón, C., Maciel, C., Varela, V., Ibarburu, S., Tarragó, L., King, P. H., Si, Y., Kwon, Y., Hermine, O., Barbeito, L., Trias, E., The pathogenic role of c-Kit⁺ mast cells in the spinal motor neuron-vascular niche in ALS. Acta Neuropathologica Communications 9 (1), 136 (2021).

Granatiero, V., Sayles, N.M., Savino, A.M., Konrad, C., Kharas, M.G., Kawamata, H., and Manfredi, G., Modulation of the IGF1R-MTOR pathway attenuates motor neuron toxicity of human ALS SOD1G93A astrocytes. Autophagy 17 (12), 4029–4042 (2021).

Wu, X., Yang, Z., Zou, J., Gao, H., Shao, Z., Li, C., and Lei, P., Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery. Signal Transduction and Targeted Therapy 10 (1), 1–38 (2025).

Salama, R. M., Abdel-Latif, G. A., Abbas, S. S., El Magdoub, H. M., and Schaalan, M. F., Neuroprotective effect of crocin against rotenone-induced Parkinson’s disease in rats: Interplay between PI3K/Akt/mTOR signaling pathway and enhanced expression of miRNA-7 and miRNA-221. Neuropharmacology 164, 107900 (2020).

Khan, M.Y., Khan, I.N., Farman, M., Karim, S.A., Qadri, I., Kamal, M.A., Ghamdi, K.A., and Harakeh, S., HTLV-1 associated neurological disorders. Current Topics in Medicinal Chemistry 17 (12), 1320–1330 (2017).

Kant, S., Stopa, E. G., Johanson, C. E., Baird, A., and Silverberg, G. D., Choroid plexus genes for CSF production and brain homeostasis are altered in Alzheimer’s disease. Fluids Barriers CNS 15 (1), 34 (2018).

Hokama, M., Oka, S., Leon, J., Ninomiya, T., Honda, H., Sasaki, K., Iwaki, T., Ohara, T., Sasaki, T., LaFerla, F. M., Kiyohara, Y., Nakabeppu, Y., Altered expression of diabetes-related genes in Alzheimer's disease brains: the Hisayama study. Cerebral Cortex 24 (9), 2476–2488 (2014).

Antonell, A., Lladó, A., Altirriba, J., Botta-Orfila, T., Balasa, M., Fernández, M., Ferrer, I., Sánchez-Valle, R., Molinuevo, J. L., A preliminary study of the whole-genome expression profile of sporadic and monogenic early-onset Alzheimer's disease. Neurobiology of Aging 34 (7), 1772–1778 (2013).

Readhead, B., Haure-Mirande, J. V., Funk, C. C., Richards, M. A., Shannon, P., Haroutunian, V., Sano, M., Liang, W. S., Beckmann, N. D., Price, N. D., Reiman, E. M., Schadt, E. E., Ehrlich, M. E., Gandy, S., Dudley, J. T., Multiscale analysis of independent Alzheimer's cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron 99 (1), 64–82.e7 (2018).

Berchtold, N. C., Coleman, C. D., Cribbs, D. H., Rogers, J., Gillen, D. L., and Cotman, C. W., Synaptic genes are extensively downregulated across multiple brain regions in normal human aging and Alzheimer’s disease. Neurobiol. Aging 34 (6), 1653–1661 (2013).

Palmieri, I., Poloni, T. E., Medici, V., Zucca, S., Davin, A., Pansarasa, O., Ceroni, M., Tronconi, L., Guaita, A., Gagliardi, S., Cereda, C., Differential neuropathology, genetics, and transcriptomics in two kindred cases with Alzheimer's disease and Lewy body dementia. Biomedicines 10 (7), 1687 (2022).

Gao, Y., Liu, J., Wang, J., Liu, Y., Zeng, L. H., Ge, W., Ma, C. Proteomic analysis of human hippocampal subfields provides new insights into the pathogenesis of Alzheimer's disease and the role of glial cells. Brain Pathol. 32 (4), e13047 (2022).

Nunez-Iglesias, J., Liu, C.-C., Morgan, T. E., Finch, C. E., and Zhou, X. J., Joint Genome-Wide Profiling of miRNA and mRNA Expression in Alzheimer’s Disease Cortex Reveals Altered miRNA Regulation. Plos One 5 (2), e8898 (2010).

Dumitriu, A., Golji, J., Labadorf, A. T., Gao, B., Beach, T. G., Myers, R. H., Longo, K. A., Latourelle, J. C. Integrative analyses of proteomics and RNA transcriptomics implicate mitochondrial processes, protein folding pathways and GWAS loci in Parkinson disease. BMC Med Genomics 9, 5 (2016).

Zaccaria, A., Antinori, S., Licker, V., Kövari, E., Lobrinus, J. A., and Burkhard, M. R., Multiomic Analyses of Dopaminergic Neurons Isolated from Human Substantia Nigra in Parkinson’s Disease: A Descriptive and Exploratory Study. Cell. Mol. Neurobiol. 42 (8), 2805–2818 (2022).

Cappelletti, C., Henriksen, S. P., Geut, H., Rozemuller, A. J. M., van de Berg, W. D. J., Pihlstrøm, L., Toft, M. Transcriptomic profiling of Parkinson's disease brains reveals disease stage specific gene expression changes. Acta Neuropathol. 146 (2), 227–244 (2023).

Lesnick, T. G., Papapetropoulos, S., Mash, D. C., Ffrench-Mullen, J., Shehadeh, L., de Andrade, M., Henley, J. R., Rocca, W. A., Ahlskog, J. E., Maraganore, D. M. A genomic pathway approach to a complex disease: axon guidance and Parkinson disease. PLoS Genet. 3 (6), e98 (2007).

Zheng, B., Liao, Z., Locascio, J. J., Lesniak, K. A., Roderick, S. S., Watt, M. L., Eklund, A. C., Zhang-James, Y., Kim, P. D., Hauser, M. A., Grünblatt, E., Moran, L. B., Mandel, S. A., Riederer, P., Miller, R. M., Federoff, H. J., Wüllner, U., Papapetropoulos, S., Youdim, M. B., Cantuti-Castelvetri, I., Young, A. B., Vance, J. M., Davis, R. L., Hedreen, J. C., Adler, C. H., Beach, T. G., Graeber, M. B., Middleton, F. A., Rochet, J. C., Scherzer, C. R.; Global PD Gene Expression (GPEX) Consortium. PGC-1α, a potential therapeutic target for early intervention in Parkinson's disease. Sci. Transl. Med. 2 (52), 52ra73 (2010).

Shtilbans, A., Choi, S. G., Fowkes, M. E., Khitrov, G., Shahbazi, M., Ting, J., Zhang, W., Sun, Y., Sealfon, S. C., Lange, D. J. Differential gene expression in patients with amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. 12 (4), 250–256 (2011).

Bernardini, C., Censi, F., Lattanzi, W., Barba, M., Calcagnini, G., Giuliani, A., Tasca, G., Sabatelli, M., Ricci, E., Michetti, F. Mitochondrial network genes in the skeletal muscle of amyotrophic lateral sclerosis patients. PLoS One 8 (2), e57739 (2013).

Krach, F., Batra, R., Wheeler, E. C., Vu, A. Q., Wang, R., Hutt, K., Rabin, S. J., Baughn, M. W., Libby, R. T., Diaz-Garcia, S., Stauffer, J., Pirie, E., Saberi, S., Rodriguez, M., Madrigal, A. A., Kohl, Z., Winner, B., Yeo, G. W., Ravits, J. Transcriptome-pathology correlation identifies interplay between TDP-43 and the expression of its kinase CK1E in sporadic ALS. Acta Neuropathol. 136 (3), 405–423 (2018).

Cox, L.E., Ferraiuolo, L., Goodall, E.F., Heath, P.R., Higginbottom, A., Mortiboys, H., Hollinger, H.C., Hartley, J.A., Brockington, A., Burness, C.E., Morrison, K.E., Wharton, S.B., Grierson, A.J., Ince, P.G., Kirby, J., Shaw, P.J., Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS). PLoS One 5 (3), e9872 (2010).

Barrett, T., Wilhite, S.E., Ledoux, P., Evangelista, C., Kim, I.F., Tomashevsky, M., Marshall, K.A., Phillippy, K.H., Sherman, P.M., Holko, M., Yefanov, A., Lee, H., Zhang, N., Robertson, C.L., Serova, N., Davis, S., Soboleva, A., NCBI GEO: archive for functional genomics data sets--update. Nucleic Acids Res. 41, D991–D995 (2013).

Bolstad, B. M., Irizarry, R. A., Astrand, M., and Speed, T. P., A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinforma. Oxf. Engl. 19 (2), 185–193 (2003).

Huber, W., Orchestrating high-throughput genomic analysis with Bioconductor. Nat Methods 12 (2), 115–121 (2015).

Ritchie, M.E., Phipson, B., Wu, D., Hu, Y., Law, C.W., Shi, W., Smyth, G.K., limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43 (7), e47 (2015).

Love, M. I., Huber, W., and Anders, S., Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15 (12), 550 (2014).

Saito, R., Smoot, M., Ono, K., Ruscheinski, J., Wang, P.-L., Lotia, S., Pico, A.R., Bader, G.D., Ideker, T., A travel guide to Cytoscape plugins. Nat Methods 9, 1069–1076 (2012).

Kamburov, A., Wierling, C., Lehrach, H., and Herwig, R., ConsensusPathDB--a database for integrating human functional interaction networks. Nucleic Acids Res. 37, D623-628 (2009).

Kanehisa, M. and Goto, S., KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res. 28 (1), 27–30 (2000).

Jassal, B., Matthews, L., Viteri, G., Gong, C., Lorente, P., Fabregat, A., Sidiropoulos, K., Cook, J., Gillespie, M., Haw, R., Loney, F., May, B., Milacic, M., Rothfels, K., Sevilla, C., Shamovsky, V., Shorser, S., Varusai, T., Weiser, J., Wu, G., Stein, L., Hermjakob, H., D'Eustachio, P., The Reactome pathway knowledgebase. Nucleic Acids Res. 48 (D1), D498–D503 (2020).