Abstract
The paper aims developing a computational framework of signaling using the principles of biochemical systems theory as a model for Parkinson’s disease. Several molecular interactions aided by TNFα, a proinflammatory cytokine play key roles in mediating glutamate excitotoxicity and neuroinflammation, resulting in neuronal cell death. In this paper, initial concentrations and rate constants were extracted from literature and simulations developed were based on systems of ordinary differential equations following first-order kinetics. In control or healthy conditions, a decrease in TNFα and neuronal cell death was predicted in simulations matching data from experiments, whereas in diseased condition, a drastic increase in levels of TNFα, glutamate, TNFR1 and ROS were observed similar to experimental data correlating diseased condition to augmented neuronal cell death. The study suggests toxic effects induced by TNFα in the substantia nigra may be attributed to Parkinson’s disease conditions.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Ji, Z., Yan, K., Li, W., Hu, H., Zhu, X.: Mathematical and computational modeling in complex biological systems. Biomed. Res. Int. 2017, 1–16 (2017)
Ray Dorsey, E., et al.: Global, regional, and national burden of Parkinson’s disease, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 17, 939–953 (2018)
Ragothaman, M., Govindappa, S.T., Rattihalli, R., Subbakrishna, D.K., Muthane, U.B.: Direct costs of managing Parkinson’s disease in india: concerns in a developing country. Mov. Disord. 21, 1755–1758 (2006)
Perez, R.G., et al.: A role for α-synuclein in the regulation of dopamine biosynthesis. J. Neurosci. 22, 3090–3099 (2002)
Sasidharakurup, H., Melethadathil, N., Nair, B., Diwakar, S.: A systems model of Parkinson’s disease using biochemical systems theory. Omics J. Integr. Biol. 21, 454–464 (2017)
Stayte, S., Vissel, B.: Advances in non-dopaminergic treatments for Parkinson’s disease. Front. Neurosci. 8, 113 (2014)
Lindenau, J.D., Altmann, V., Schumacher-Schuh, A.F., Rieder, C.R., Hutz, M.H.: Tumor necrosis factor alpha polymorphisms are associated with Parkinson’s disease age at onset. Neurosci. Lett. 658, 133–136 (2017)
Nagatsu, T., Sawada, M.: Biochemistry of postmortem brains in Parkinson’s disease: historical overview and future prospects. J. Neural Transm. Suppl. 113–120 (2007). https://doi.org/10.1007/978-3-211-73574-9-14
Peter, I., et al.: Anti-tumor necrosis factor therapy and incidence of Parkinson disease among patients with inflammatory bowel disease. JAMA Neurol. 75, 939 (2018)
Harms, A.S., et al.: Delayed dominant-negative TNF gene therapy halts progressive loss of nigral dopaminergic neurons in a rat model of Parkinson’s disease. Mol. Ther. 19, 46–52 (2011)
Wood, L.B., Winslow, A.R., Strasser, S.D., Wood, L., Israel, B.: Systems biology of neurodegenerative diseases graphical abstract HHS public access. Integr. Biol. (Camb.) 7, 758–775 (2015)
Clark, I.: How TNF was recognized as a key mechanism of disease. Cytokine Growth Factor Rev. 18, 335–343 (2007)
Parent, A., Parent, M., Charara, A.: Glutamatergic inputs to midbrain dopaminergic neurons in primates. Parkinsonism Relat. Disord. 5, 193–201 (1999)
Kouchaki, E., et al.: Increased serum levels of TNF-α and decreased serum levels of IL-27 in patients with Parkinson disease and their correlation with disease severity. Clin. Neurol. Neurosurg. 166, 76–79 (2018)
Izumi, Y., et al.: Vulnerability to glutamate toxicity of dopaminergic neurons is dependent on endogenous dopamine and MAPK activation. J. Neurochem. 110, 745–755 (2009)
Hanisch, U.-K.: Microglia as a source and target of cytokines. Glia 40, 140–155 (2002)
Takeuchi, H., et al.: Tumor necrosis factor-α induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J. Biol. Chem. 281, 21362–21368 (2006)
Bezzi, P., et al.: CXCR18-activated astrocyte glutamate release via TNFα: amplification by microglia triggers neurotoxicity. Nat. Neurosci. 4, 702–710 (2001)
Dufty, B.M., et al.: Calpain-cleavage of α-synuclein: connecting proteolytic processing to disease-linked aggregation. Am. J. Pathol. 170, 1725–1738 (2007)
Smith, P.D., et al.: Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson’s disease. Proc. Natl. Acad. Sci. 100, 13650–13655 (2003)
Inoue, K.: Microglial activation by purines and pyrimidines. Glia 40, 156–163 (2002)
Negro, S., et al.: ATP released by injured neurons activates Schwann cells. Front. Cell. Neurosci. 10, 134 (2016)
Welser-Alves, J.V., Milner, R.: Microglia are the major source of TNF-α and TGF-β1 in postnatal glial cultures; regulation by cytokines, lipopolysaccharide, and vitronectin. Neurochem. Int. 63, 47–53 (2013)
Vincent, V.A.M., Tilders, F.J.H., Dam, A.V.A.N.: Inhibition of endotoxin-induced nitric oxide synthase production in microglial cells by the presence of astroglial cells: a role for transforming growth factor β. Glia 198, 190–198 (1997)
Cabezas, R., et al.: Astrocytes role in Parkinson: a double-edged sword (2013). https://doi.org/10.5772/54305
Junn, E., Mouradian, M.M.: Apoptotic signaling in dopamine-induced cell death: the role of oxidative stress, p38 mitogen-activated protein kinase, cytochrome c and caspases. J. Neurochem. 78, 374–383 (2001)
Hirsch, E.C.: Glial cells and Parkinson’ s disease. J. Neurol. 247, 58–62 (2000)
Qian, L., Flood, P.M.: Microglial cells and Parkinson’s disease. Immunol. Res. 41, 155–164 (2008)
He, J., Zhong, W., Zhang, M., Zhang, R., Hu, W.: P38 mitogen-activated protein kinase and Parkinson’s disease. Transl. Neurosci. 9, 147 (2018)
Knorre, W.: M. A. Savageau, Biochemical Systems Analysis. A Study of Function and Design in Molecular Biology. 396 S., 115 Abb., 14 Tab. Reading, Mass. 1976. Addison-Wesley Pbl. Co./Advanced Book Program. £ 26,50. Z. Allg. Mikrobiol. 19, 149–150 (2007)
Olmos, G., Lladó, J.: Tumor necrosis factor alpha: a link between neuroinflammation and excitotoxicity. Mediat. Inflamm. 2014 (2014)
Leal, M.C., Casabona, J.C., Puntel, M., Pitossi, F.: Interleukin-1β and TNF-α: reliable targets for protective therapies in Parkinson’s disease? Front. Cell. Neurosci. 7, 53 (2013)
Fischer, R., Maier, O.: Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF. Oxidative Med. Cell. Longev. 2015, 1–18 (2015)
Acknowledgements
This work derives direction and ideas from the Chancellor of Amrita University, Sri Mata Amritanandamayi Devi. This work was partially funded by Department of Science and Technology Grant DST/CSRI/2017/31, Government of India and by Embracing the World Research-for-a-Cause initiative.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2020 Springer Nature Switzerland AG
About this paper
Cite this paper
Sasidharakurup, H., Nair, L., Bhaskar, K., Diwakar, S. (2020). Computational Modelling of TNFα Pathway in Parkinson’s Disease – A Systemic Perspective. In: Cherifi, H., Gaito, S., Mendes, J., Moro, E., Rocha, L. (eds) Complex Networks and Their Applications VIII. COMPLEX NETWORKS 2019. Studies in Computational Intelligence, vol 882. Springer, Cham. https://doi.org/10.1007/978-3-030-36683-4_61
Download citation
DOI: https://doi.org/10.1007/978-3-030-36683-4_61
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-36682-7
Online ISBN: 978-3-030-36683-4
eBook Packages: Intelligent Technologies and RoboticsIntelligent Technologies and Robotics (R0)