Skip to main content
SpringerLink
Log in

Omics Analyses in a Neural Stem Cell Model of Familial Parkinson’s Disease

  • Conference paper
  • First Online:
GeNeDis 2022 (GeNeDis 2022)

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1423))

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting millions of people worldwide. Despite considerable efforts, the underlying pathological mechanisms remain elusive, and yet, no treatment has been developed to efficiently reverse or modify disease progression. Thus, new experimental models are required to provide insights into the pathology of PD. Small-molecule neural precursor cells (smNPCs) are ideal for the study of neurodegenerative disorders due to their neural identity and stem cell properties. Cytoplasmic aggregates of α-synuclein (αSyn) are considered a hallmark of PD and a point mutation in the gene encoding p.A53T is responsible for a familial PD form with earlier and robust symptom onset. In order to study the cellular pathology of PD, we genetically modified smNPCs to inducibly overexpress EYFP-SNCA A53T. This cellular model was biochemically characterized, while dysregulated biological pathways and key regulators of PD pathology were identified by computational analyses. Our study indicates three novel genes, UBA52, PIP5K1A, and RPS2, which may mediate PD cellular pathology.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. R. Cacabelos, “Parkinson’s Disease: From Pathogenesis to Pharmacogenomics,” Int J Mol Sci, vol. 18, no. 3, Mar. 2017, doi: 10.3390/IJMS18030551.

    Google Scholar 

  2. J. Parkinson, “An Essay on the Shaking Palsy,” J Neuropsychiatry Clin Neurosci, vol. 14, no. 2, 2002.

    Google Scholar 

  3. E. R. Dorsey, T. Sherer, M. S. Okun, and B. R. Bloem, “The Emerging Evidence of the Parkinson Pandemic,” J Parkinsons Dis, vol. 8, pp. 3–8, 2018, doi: https://doi.org/10.3233/JPD-181474.

  4. V. L. Feigin et al., “Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015,” Lancet Neurol, vol. 16, no. 11, pp. 877– 897, Nov. 2017, doi: https://doi.org/10.1016/S1474-4422(17)30299-5.

  5. E. R. Dorsey and B. R. Bloem, “The Parkinson Pandemic—A Call to Action,” JAMA Neurol, vol. 75, no. 1, 9–10, Jan. 2018, doi: https://doi.org/10.1001/JAMANEUROL.2017.3299.

  6. J. Jankovic, “Parkinson’s disease: Clinical features and diagnosis,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 79, no. 4. BMJ Publishing Group, pp. 368–376, 2008. https://doi.org/10.1136/jnnp.2007.131045.

  7. S. Sveinbjornsdottir, “The clinical symptoms of Parkinson’s disease,” Journal of Neurochemistry. Blackwell Publishing Ltd, pp. 318–324, Oct. 01, 2016. https://doi.org/10.1111/jnc.13691.

  8. M. J. Armstrong and M. S. Okun, “Diagnosis and Treatment of Parkinson Disease: A Review,” JAMA - Journal of the American Medical Association, vol. 323, no. 6, pp. 548–560, Feb. 2020, https://doi.org/10.1001/JAMA.2019.22360.

  9. M. Emre et al., “Rivastigmine for Dementia Associated with Parkinson’s Disease,” vol. 351, no. 24, pp. 2509–2518, Dec. 2004, doi: https://doi.org/10.1056/NEJMOA041470.

  10. S. H. Fox et al., “International Parkinson and movement disorder society evidence-based medicine review: Update on treatments for the motor symptoms of Parkinson’s disease,” Movement Disorders, vol. 33, no. 8, 1248–1266, Aug. 2018, doi: https://doi.org/10.1002/MDS.27372.

  11. Ascherio and M. A. Schwarzschild, “The epidemiology of Parkinson’s disease: risk factors and prevention,” Lancet Neurol, vol. 15, no. 12, pp. 1257–1272, Nov. 2016, https://doi.org/10.1016/S1474-4422(16)30230-7.

  12. Delamarre and W. G. Meissner, “Epidemiology, environmental risk factors and genetics of Parkinson’s disease,” Presse Med, vol. 46, no. 2 Pt 1, pp. 175–181, Mar. 2017, doi: https://doi.org/10.1016/J.LPM.2017.01.001.

    Article  Google Scholar 

  13. O. B. Tysnes and A. Storstein, “Epidemiology of Parkinson’s disease,” J Neural Transm, vol. 124, no. 8, pp. 901–905, Aug. 2017, https://doi.org/10.1007/s00702-017-1686-y.

  14. M. H. Polymeropoulos et al., “Mapping of a gene for Parkinson’s disease to chromosome 4q21-q23,” Science, vol. 274, no. 5290, pp. 1197–1199, Nov. 1996, https://doi.org/10.1126/SCIENCE.274.5290.1197.

  15. M. H. Polymeropoulos et al., “Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease,” Science, vol. 276, no. 5321, pp. 2045–2047, Jun. 1997, https://doi.org/10.1126/SCIENCE.276.5321.2045.

  16. Oczkowska, W. Kozubski, M. Lianeri, and J. Dorszewska, “Mutations in PRKN and SNCA Genes Important for the Progress of Parkinson’s Disease,” Curr Genomics, vol. 14, no. 8, p. 502, Feb. 2013, https://doi.org/10.2174/1389202914666131210205839.

  17. Puschmann et al., “A Swedish family with de novo α-synuclein A53T mutation: Evidence for early cortical dysfunction,” Parkinsonism Relat Disord, vol. 15, no. 9, p. 627, Nov. 2009, https://doi.org/10.1016/J.PARKRELDIS.2009.06.007.

  18. N. Tambasco, P. Nigro, M. Romoli, P. Prontera, S. Simoni, and P. Calabresi, “A53T in a parkinsonian family: clinical update of the SNCA phenotypes,” J Neural Transm (Vienna), vol. 123, no. 11, pp. 1301–1307, Nov. 2016, https://doi.org/10.1007/S00702-016-1578-6.

  19. J. Siddiqui, N. Pervaiz, and A. A. Abbasi, “The Parkinson Disease gene SNCA: Evolutionary and structural insights with pathological implication,” Sci Rep, vol. 6, Apr. 2016, doi: 10.1038/SREP24475.

    Google Scholar 

  20. Lunati, S. Lesage, and A. Brice, “The genetic landscape of Parkinson’s disease,” Rev Neurol (Paris), vol. 174, no. 9, pp. 628–643, Nov. 2018, https://doi.org/10.1016/J.NEUROL.2018.08.004.

  21. R. L. Perlman, “Mouse models of human disease: An evolutionary perspective,” Evol Med Public Health, vol. 2016, no. 1, p. 170, Apr. 2016, https://doi.org/10.1093/EMPH/EOW014.

  22. P. O. Fernagut and M. F. Chesselet, “Alpha-synuclein and transgenic mouse models,” Neurobiol Dis, vol. 17, no. 2, pp. 123–130, Nov. 2004, https://doi.org/10.1016/J.NBD.2004.07.001.

  23. Recasens, A. Ulusoy, P. J. Kahle, D. A. di Monte, and B. Dehay, “In vivo models of alpha-synuclein transmission and propagation,” Cell and Tissue Research 2017 373:1, vol. 373, no. 1, pp. 183–193, Nov. 2017, https://doi.org/10.1007/S00441-017-2730-9.

  24. T. M. Dawson, H. S. Ko, and V. L. Dawson, “Genetic animal models of Parkinson’s disease,” Neuron, vol. 66, no. 5, pp. 646–661, Jun. 2010, https://doi.org/10.1016/J.NEURON.2010.04.034.

  25. S. Duty and P. Jenner, “Animal models of Parkinson’s disease: a source of novel treatments and clues to the cause of the disease,” Br J Pharmacol, vol. 164, no. 4, p. 1357, Oct. 2011, https://doi.org/10.1111/J.1476-5381.2011.01426.X.

  26. E. Braungart, M. Gerlach, P. Riederer, R. Baumeister, and M. C. Hoener, “Caenorhabditis elegans MPP+ model of Parkinson’s disease for high-throughput drug screenings,” Neurodegener Dis, vol. 1, no. 4–5, pp. 175–183, 2004, https://doi.org/10.1159/000080983.

  27. T. Kuwahara et al., “Familial Parkinson mutant alpha-synuclein causes dopamine neuron dysfunction in transgenic Caenorhabditis elegans,” J Biol Chem, vol. 281, no. 1, pp. 334–340, Jan. 2006, https://doi.org/10.1074/JBC.M504860200.

  28. E. R. Sawin, R. Ranganathan, and H. R. Horvitz, “C. elegans locomotory rate is modulated by the environment through a dopaminergic pathway and by experience through a serotonergic pathway,” Neuron, vol. 26, no. 3, pp. 619–631, 2000, https://doi.org/10.1016/S0896-6273(00)81199-X.

  29. D. F. Lázaro, M. A. S. Pavlou, and T. F. Outeiro, “Cellular models as tools for the study of the role of alpha-synuclein in Parkinson’s disease,” Exp Neurol, vol. 298, pp. 162–171, Dec. 2017, https://doi.org/10.1016/J.EXPNEUROL.2017.05.007.

  30. H. Xicoy, B. Wieringa, and G. J. M. Martens, “The SH-SY5Y cell line in Parkinson’s disease research: a systematic review,” Mol Neurodegener, vol. 12, no. 1, pp. 1–11, Jan. 2017, https://doi.org/10.1186/S13024-017-0149-0/TABLES/4.

  31. Q. Zhang, W. Chen, S. Tan, and T. Lin, “Stem Cells for Modeling and Therapy of Parkinson’s Disease,” Hum Gene Ther, vol. 28, no. 1, pp. 85–98, Jan. 2017, https://doi.org/10.1089/HUM.2016.116.

  32. S. Assou et al., “Recurrent Genetic Abnormalities in Human Pluripotent Stem Cells: Definition and Routine Detection in Culture Supernatant by Targeted Droplet Digital PCR,” Stem Cell Reports, vol. 14, pp. 1–8, 2020, https://doi.org/10.1016/j.stemcr.2019.12.004.

  33. Okita, M. Nakagawa, H. Hyenjong, T. Ichisaka, and S. Yamanaka, “Generation of mouse induced pluripotent stem cells without viral vectors,” Science, vol. 322, no. 5903, pp. 949–953, Nov. 2008, https://doi.org/10.1126/SCIENCE.1164270.

  34. P. Reinhardt et al., “Derivation and Expansion Using Only Small Molecules of Human Neural Progenitors for Neurodegenerative Disease Modeling,” PLoS One, vol. 8, no. 3, p. e59252, Mar. 2013, doi: 10.1371/journal.pone.0059252.

    Google Scholar 

  35. S. Petrakis et al., “Gateway-compatible transposon vector to genetically modify human embryonic kidney and adipose-derived stromal cells.,” Biotechnol J, vol. 7, no. 7, pp. 891–897, Jul. 2012, https://doi.org/10.1002/biot.201100471.

  36. T. Lamark and T. Johansen, “Aggrephagy: selective disposal of protein aggregates by macroautophagy,” Int J Cell Biol, vol. 2012, 2012, https://doi.org/10.1155/2012/736905.

  37. H. R. Yun, Y. H. Jo, J. Kim, Y. Shin, S. S. Kim, and T. G. Choi, “Roles of Autophagy in Oxidative Stress,” Int J Mol Sci, vol. 21, no. 9, May 2020, https://doi.org/10.3390/IJMS21093289.

  38. Y. Feng, D. He, Z. Yao, and D. J. Klionsky, “The machinery of macroautophagy,” Cell Research 2014 24:1, vol. 24, no. 1, pp. 24–41, Dec. 2013, doi: https://doi.org/10.1038/cr.2013.168.

  39. N. Fujikake, M. Shin, and S. Shimizu, “Association between autophagy and neurodegenerative diseases,” Front Neurosci, vol. 12, no. MAY, p. 255, May 2018, https://doi.org/10.3389/FNINS.2018.00255/BIBTEX.

  40. X. Hou, J. O. Watzlawik, F. C. Fiesel, and W. Springer, “Autophagy in Parkinson’s Disease,” J Mol Biol, vol. 432, no. 8, pp. 2651–2672, Apr. 2020, https://doi.org/10.1016/J.JMB.2020.01.037.

  41. Liu and L. Li, “Targeting Autophagy for the Treatment of Alzheimer’s Disease: Challenges and Opportunities,” Front Mol Neurosci, vol. 12, p. 203, Aug. 2019, https://doi.org/10.3389/FNMOL.2019.00203/BIBTEX.

  42. D. D. O. Martin, S. Ladha, D. E. Ehrnhoefer, and M. R. Hayden, “Autophagy in Huntington disease and huntingtin in autophagy,” Trends Neurosci, vol. 38, pp. 26–35, 2015, https://doi.org/10.1016/j.tins.2014.09.003.

  43. R. A. Nixon, “The role of autophagy in neurodegenerative disease,” Nature Medicine 2013 19:8, vol. 19, no. 8, pp. 983–997, Aug. 2013, https://doi.org/10.1038/nm.3232.

  44. Kobayashi et al., “The ubiquitin hybrid gene UBA52 regulates ubiquitination of ribosome and sustains embryonic development,” Sci Rep, vol. 6, Nov. 2016, https://doi.org/10.1038/SREP36780.

  45. F. Simunovic et al., “Gene expression profiling of substantia nigra dopamine neurons: further insights into Parkinson’s disease pathology,” Brain, vol. 132, no. 7, p. 1795, Jul. 2009, https://doi.org/10.1093/BRAIN/AWN323.

  46. J. Lodhi and C. F. Semenkovich, “Peroxisomes: a Nexus for Lipid Metabolism and Cellular Signaling,” Cell Metab, vol. 19, no. 3, p. 380, Mar. 2014, https://doi.org/10.1016/J.CMET.2014.01.002.

  47. Rodríguez-Berdini and B. L. Caputto, “Lipid metabolism in neurons: A brief story of a novel c-Fos-dependent mechanism for the regulation of their synthesis,” Front Cell Neurosci, vol. 13, p. 198, Apr. 2019, https://doi.org/10.3389/FNCEL.2019.00198/XML/NLM.

  48. V. I. Titorenko and S. R. Terlecky, “Peroxisome Metabolism and Cellular Aging,” Traffic, vol. 12, no. 3, pp. 252–259, Mar. 2011, https://doi.org/10.1111/J.1600-0854.2010.01144.X.

  49. W. Cui, D. Liu, W. Gu, and B. Chu, “Peroxisome-driven ether-linked phospholipids biosynthesis is essential for ferroptosis,” Cell Death & Differentiation 2021 28:8, vol. 28, no. 8, pp. 2536–2551, Mar. 2021, https://doi.org/10.1038/s41418-021-00769-0.

  50. L. Mahoney-Sanchez et al., “Alpha synuclein determines ferroptosis sensitivity in dopaminergic neurons via modulation of ether-phospholipid membrane composition,” Cell Rep, vol. 40, no. 8, p. 111231, Aug. 2022, https://doi.org/10.1016/J.CELREP.2022.111231.

  51. D. Tang and G. Kroemer, “Peroxisome: the new player in ferroptosis”, https://doi.org/10.1038/s41392-020-00404-3.

  52. Y. Zou et al., “Plasticity of ether lipids promotes ferroptosis susceptibility and evasion,” Nature, vol. 585, no. 7826, pp. 603–608, Sep. 2020, https://doi.org/10.1038/S41586-020-2732-8.

  53. Hu et al., “Resolution of structure of PIP5K1A reveals molecular mechanism for its regulation by dimerization and dishevelled,” Nature Communications 2015 6:1, vol. 6, no. 1, pp. 1–11, Sep. 2015, https://doi.org/10.1038/ncomms9205.

  54. Mandal, “Review of PIP2 in Cellular Signaling, Functions and Diseases,” Int J Mol Sci, vol. 21, no. 21, pp. 1–20, Nov. 2020, https://doi.org/10.3390/IJMS21218342.

  55. S. Chinnarasu, F. Alogaili, K. E. Bove, A. Jaeschke, and D. Y. Hui, “Hepatic LDL receptor-related protein-1 deficiency alters mitochondrial dynamics through phosphatidylinositol 4,5-bisphosphate reduction,” J Biol Chem, vol. 296, Jan. 2021, https://doi.org/10.1016/J.JBC.2021.100370.

  56. J. Dong and A. G. Hinnebusch, “uS5/Rps2 residues at the 40S ribosome entry channel enhance initiation at suboptimal start codons in vivo,” Genetics, vol. 220, no. 1, Jan. 2022, https://doi.org/10.1093/GENETICS/IYAB176.

  57. Y. Li et al., “Glycerol-Induced Powdery Mildew Resistance in Wheat by Regulating Plant Fatty Acid Metabolism, Plant Hormones Cross-Talk, and Pathogenesis-Related Genes,” International Journal of Molecular Sciences 2020, Vol. 21, Page 673, vol. 21, no. 2, p. 673, Jan. 2020, https://doi.org/10.3390/IJMS21020673.

  58. S. E. Sattler, L. Mène-Saffrané, E. E. Farmer, M. Krischke, M. J. Mueller, and D. DellaPenna, “Nonenzymatic Lipid Peroxidation Reprograms Gene Expression and Activates Defense Markers in Arabidopsis Tocopherol-Deficient Mutants,” Plant Cell, vol. 18, no. 12, p. 3706, 2006, https://doi.org/10.1105/TPC.106.044065.

  59. D. Shcherbakov et al., “Ribosomal mistranslation leads to silencing of the unfolded protein response and increased mitochondrial biogenesis,” Commun Biol, vol. 2, no. 1, Dec. 2019, https://doi.org/10.1038/S42003-019-0626-9.

Download references

Acknowledgments

Plasmids pCMV(CAT)T7-SB100 and pDONR223-SNCA A53T were kindly provided by Dr. Zsuzsanna Izsvak and Prof. Dr. Erich Wanker, respectively. CIISB, Instruct-CZ Centre of Instruct-ERIC EU consortium, funded by MEYS CR infrastructure project LM2018127, is gratefully acknowledged for the financial support of the measurements at the CF CEITEC/Brno - Proteomics.

Author information

Authors and Affiliations

  1. Institute of Applied Biosciences, CERTH, Thessaloniki, Greece

    Sofia Notopoulou, Ioannis Gkekas & Spyros Petrakis

Authors
  1. Sofia Notopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ioannis Gkekas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Spyros Petrakis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sofia Notopoulou .

Editor information

Editors and Affiliations

  1. Department of Informatics, Ionian University, Corfu, Greece

    Panagiotis Vlamos

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this paper

Check for updates. Verify currency and authenticity via CrossMark

Cite this paper

Notopoulou, S., Gkekas, I., Petrakis, S. (2023). Omics Analyses in a Neural Stem Cell Model of Familial Parkinson’s Disease. In: Vlamos, P. (eds) GeNeDis 2022. GeNeDis 2022. Advances in Experimental Medicine and Biology, vol 1423. Springer, Cham. https://doi.org/10.1007/978-3-031-31978-5_12

Download citation

Publish with us

Policies and ethics

Search

Navigation