Int J Stem Cells.  2025 Feb;18(1):21-36. 10.15283/ijsc23169.

Stem Cell-Based Approaches in Parkinson’s Disease Research

• Kim MS
• Yoon S
• Choi J
• Kim YJ
• Lee G

• KMID: 2565194
• DOI: http://doi.org/10.15283/ijsc23169

Abstract

Parkinson’s disease (PD) is a neurodegenerative condition characterized by the loss of midbrain dopaminergic neurons, leading to motor symptoms. While current treatments provide limited relief, they don’t alter disease progression. Stem cell technology, involving patient-specific stem cell-derived neurons, offers a promising avenue for research and personalized regenerative therapies. This article reviews the potential of stem cell-based research in PD, summarizing ongoing efforts, their limitations, and introducing innovative research models. The integration of stem cell technology and advanced models promises to enhance our understanding and treatment strategies for PD.

Keyword

Disease model; Parkinson disease; Stem cell therapy; Pathological mechanism

Figure

• 

  Fig. 1 The pathogenesis of Parkinson’s disease. α-syn: α-synuclein.

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  Fig. 2 Stem cell-based therapy and disease modeling. hPSCs: human pluripotent stem cells.

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  Fig. 3 The optogenetics-assisted alpha-synuclein aggregation induction system (OASIS) model. α-syn: α-synuclein.

Reference

References

1. Dauer W, Przedborski S. 2003; Parkinson's disease: mechanisms and models. Neuron. 39:889–909. DOI: 10.1016/S0896-6273(03)00568-3. PMID: 12971891.

2. Olanow CW, Tatton WG. 1999; Etiology and pathogenesis of Parkinson's disease. Annu Rev Neurosci. 22:123–144. DOI: 10.1146/annurev.neuro.22.1.123. PMID: 10202534.

3. Polymeropoulos MH, Lavedan C, Leroy E, et al. 1997; Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 276:2045–2047. DOI: 10.1126/science.276.5321.2045. PMID: 9197268.

4. Singleton AB, Farrer M, Johnson J, et al. 2003; α-Synuclein locus triplication causes Parkinson's disease. Science. 302:841. DOI: 10.1126/science.1090278. PMID: 14593171.

5. Lee VM, Trojanowski JQ. 2006; Mechanisms of Parkinson's disease linked to pathological alpha-synuclein: new targets for drug discovery. Neuron. 52:33–38. DOI: 10.1016/j.neuron.2006.09.026. PMID: 17015225.

6. Henderson MX, Trojanowski JQ, Lee VM. 2019; α-Synuclein pathology in Parkinson's disease and related α-synucleinopathies. Neurosci Lett. 709:134316. DOI: 10.1016/j.neulet.2019.134316. PMID: 31170426. PMCID: PMC7014913.

7. Basellini MJ, Kothuis JM, Comincini A, Pezzoli G, Cappelletti G, Mazzetti S. 2023; Pathological pathways and alpha-synuclein in Parkinson's disease: a view from the periphery. Front Biosci (Landmark Ed). 28:33. DOI: 10.31083/j.fbl2802033. PMID: 36866559.

8. Golpich M, Amini E, Mohamed Z, Azman Ali R, Mohamed Ibrahim N, Ahmadiani A. 2017; Mitochondrial dysfunction and biogenesis in neurodegenerative diseases: pathogenesis and treatment. CNS Neurosci Ther. 23:5–22. DOI: 10.1111/cns.12655. PMID: 27873462. PMCID: PMC6492703.

9. Hu Q, Wang G. 2016; Mitochondrial dysfunction in Parkinson's disease. Transl Neurodegener. 5:14. DOI: 10.1186/s40035-016-0060-6. PMID: 27453777. PMCID: PMC4957882.

10. Schapira AH. 2007; Mitochondrial dysfunction in Parkinson's disease. Cell Death Differ. 14:1261–1266. DOI: 10.1038/sj.cdd.4402160. PMID: 17464321.

11. Wang Q, Liu Y, Zhou J. 2015; Neuroinflammation in Parkinson's disease and its potential as therapeutic target. Transl Neurodegener. 4:19. DOI: 10.1186/s40035-015-0042-0. PMID: 26464797. PMCID: PMC4603346.

12. Ebrahimi-Fakhari D, Cantuti-Castelvetri I, Fan Z, et al. 2011; Distinct roles in vivo for the ubiquitin-proteasome system and the autophagy-lysosomal pathway in the degradation of α-synuclein. J Neurosci. 31:14508–14520. DOI: 10.1523/JNEUROSCI.1560-11.2011. PMID: 21994367. PMCID: PMC3587176.

13. Kulkarni A, Preeti K, Tryphena KP, Srivastava S, Singh SB, Khatri DK. 2023; Proteostasis in Parkinson's disease: recent development and possible implication in diagnosis and therapeutics. Ageing Res Rev. 84:101816. DOI: 10.1016/j.arr.2022.101816. PMID: 36481490.

14. Pickrell AM, Youle RJ. 2015; The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease. Neuron. 85:257–273. DOI: 10.1016/j.neuron.2014.12.007. PMID: 25611507. PMCID: PMC4764997.

15. Srinivasan E, Chandrasekhar G, Chandrasekar P, et al. 2021; Alpha-synuclein aggregation in Parkinson's disease. Front Med (Lausanne). 8:736978. DOI: 10.3389/fmed.2021.736978. PMID: 34733860. PMCID: PMC8558257.

16. Chu YT, Tai CH, Lin CH, Wu RM. 2021; Updates on the genetics of Parkinson's disease: clinical implications and future treatment. Acta Neurol Taiwan. 30:83–93.

17. Connolly BS, Lang AE. 2014; Pharmacological treatment of Parkinson disease: a review. JAMA. 311:1670–1683. DOI: 10.1001/jama.2014.3654. PMID: 24756517.

18. Olanow CW, Stern MB, Sethi K. 2009; The scientific and clinical basis for the treatment of Parkinson disease (2009). Neurology. 72(21 Suppl 4):S1–S136. DOI: 10.1212/WNL.0b013e3181a1d44c.

19. Cheong SL, Federico S, Spalluto G, Klotz KN, Pastorin G. 2019; The current status of pharmacotherapy for the treatment of Parkinson's disease: transition from single-target to multitarget therapy. Drug Discov Today. 24:1769–1783. DOI: 10.1016/j.drudis.2019.05.003. PMID: 31102728.

20. LeWitt PA, Fahn S. 2016; Levodopa therapy for Parkinson disease: a look backward and forward. Neurology. 86(14 Suppl 1):S3–S12. DOI: 10.1212/WNL.0000000000002509. PMID: 27044648.

21. Stocchi F, Tagliati M, Olanow CW. 2008; Treatment of levodopa-induced motor complications. Mov Disord. 23 Suppl 3:S599–S612. DOI: 10.1002/mds.22052. PMID: 18781681.

22. Parkinson Study Group. 2004; A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol. 61:561–566. DOI: 10.1001/archneur.61.4.561. PMID: 15096406.

23. Siddiqi SH, Abraham NK, Geiger CL, Karimi M, Perlmutter JS, Black KJ. 2016; The human experience with intravenous levodopa. Front Pharmacol. 6:307. DOI: 10.3389/fphar.2015.00307. PMID: 26779024. PMCID: PMC4701937.

24. Freckelton I. 2022; Parkinson's disease and the criminal justice system. J Law Med. 29:309–321.

25. Chaudhuri KR, Odin P, Antonini A, Martinez-Martin P. 2011; Parkinson's disease: the non-motor issues. Parkinsonism Relat Disord. 17:717–723. DOI: 10.1016/j.parkreldis.2011.02.018. PMID: 21741874.

26. Oertel WH. 2017; Recent advances in treating Parkinson's disease. F1000Res. 6:260. DOI: 10.12688/f1000research.10100.1. PMID: 28357055. PMCID: PMC5357034.

27. Sivandzade F, Cucullo L. 2021; Regenerative stem cell therapy for neurodegenerative diseases: an overview. Int J Mol Sci. 22:2153. DOI: 10.3390/ijms22042153. PMID: 33671500. PMCID: PMC7926761.

28. Liu G, David BT, Trawczynski M, Fessler RG. 2020; Advances in pluripotent stem cells: history, mechanisms, technologies, and applications. Stem Cell Rev Rep. 16:3–32. DOI: 10.1007/s12015-019-09935-x. PMID: 31760627. PMCID: PMC6987053.

29. Barbuti PA, Barker RA, Brundin P, et al. MDS Scientific Issues Committee. 2021; Recent advances in the development of stem-cell-derived dopaminergic neuronal transplant therapies for Parkinson's disease. Mov Disord. 36:1772–1780. DOI: 10.1002/mds.28628. PMID: 33963552.

30. Lie DC, Dziewczapolski G, Willhoite AR, Kaspar BK, Shults CW, Gage FH. 2002; The adult substantia nigra contains progenitor cells with neurogenic potential. J Neurosci. 22:6639–6649. DOI: 10.1523/JNEUROSCI.22-15-06639.2002. PMID: 12151543. PMCID: PMC6758128.

31. Cha Y, Park TY, Leblanc P, Kim KS. 2023; Current status and future perspectives on stem cell-based therapies for Parkinson's disease. J Mov Disord. 16:22–41. DOI: 10.14802/jmd.22141. PMID: 36628428. PMCID: PMC9978267.

32. Palmer TD, Takahashi J, Gage FH. 1997; The adult rat hippocampus contains primordial neural stem cells. Mol Cell Neurosci. 8:389–404. DOI: 10.1006/mcne.1996.0595. PMID: 9143557.

33. Kempermann G, Wiskott L, Gage FH. 2004; Functional significance of adult neurogenesis. Curr Opin Neurobiol. 14:186–191. DOI: 10.1016/j.conb.2004.03.001. PMID: 15082323.

34. Fallon J, Reid S, Kinyamu R, et al. 2000; In vivo induction of massive proliferation, directed migration, and differentiation of neural cells in the adult mammalian brain. Proc Natl Acad Sci U S A. 97:14686–14691. DOI: 10.1073/pnas.97.26.14686. PMID: 11121069. PMCID: PMC18979.

35. Zhao M, Momma S, Delfani K, et al. 2003; Evidence for neurogenesis in the adult mammalian substantia nigra. Proc Natl Acad Sci U S A. 100:7925–7930. DOI: 10.1073/pnas.1131955100. PMID: 12792021. PMCID: PMC164689.

36. Palmer TD, Schwartz PH, Taupin P, Kaspar B, Stein SA, Gage FH. 2001; Cell culture. Progenitor cells from human brain after death. Nature. 411:42–43. DOI: 10.1038/35075141. PMID: 11333968.

37. Parmar M, Skogh C, Englund U. 2003; A transplantation study of expanded human embryonic forebrain precursors: evidence for selection of a specific progenitor population. Mol Cell Neurosci. 23:531–543. DOI: 10.1016/S1044-7431(03)00097-6. PMID: 12932435.

38. De Gioia R, Biella F, Citterio G, et al. 2020; Neural stem cell transplantation for neurodegenerative diseases. Int J Mol Sci. 21:3103. DOI: 10.3390/ijms21093103. PMID: 32354178. PMCID: PMC7247151.

39. Björklund A, Dunnett SB, Brundin P, et al. 2003; Neural transplantation for the treatment of Parkinson's disease. Lancet Neurol. 2:437–445. DOI: 10.1016/S1474-4422(03)00442-3. PMID: 12849125.

40. Andersson EK, Irvin DK, Ahlsiö J, Parmar M. 2007; Ngn2 and Nurr1 act in synergy to induce midbrain dopaminergic neurons from expanded neural stem and progenitor cells. Exp Cell Res. 313:1172–1180. DOI: 10.1016/j.yexcr.2006.12.014. PMID: 17291494.

41. Parmar M, Li M. 2007; Early specification of dopaminergic phenotype during ES cell differentiation. BMC Dev Biol. 7:86. DOI: 10.1186/1471-213X-7-86. PMID: 17640353. PMCID: PMC1978208.

42. Ganat YM, Calder EL, Kriks S, et al. 2012; Identification of embryonic stem cell-derived midbrain dopaminergic neurons for engraftment. J Clin Invest. 122:2928–2939. DOI: 10.1172/JCI58767. PMID: 22751106. PMCID: PMC3408729.

43. Stoker TB, Barker RA. 2020; Recent developments in the treatment of Parkinson's disease. F1000Res. 9:F1000 Faculty Rev-862. DOI: 10.12688/f1000research.25634.1. PMID: 32789002. PMCID: PMC7400683.

44. Yamanaka S. 2020; Pluripotent stem cell-based cell therapy-promise and challenges. Cell Stem Cell. 27:523–531. DOI: 10.1016/j.stem.2020.09.014. PMID: 33007237.

45. Kriks S, Shim JW, Piao J, et al. 2011; Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature. 480:547–551. DOI: 10.1038/nature10648. PMID: 22056989. PMCID: PMC3245796.

46. Kim TW, Piao J, Koo SY, et al. 2021; Biphasic activation of WNT signaling facilitates the derivation of midbrain dopamine neurons from hESCs for translational use. Cell Stem Cell. 28:343–355.e5. DOI: 10.1016/j.stem.2021.01.005. PMID: 33545081. PMCID: PMC8006469.

47. Schweitzer JS, Song B, Herrington TM, et al. 2020; Personalized iPSC-derived dopamine progenitor cells for Parkinson's disease. N Engl J Med. 382:1926–1932. DOI: 10.1056/NEJMoa1915872. PMID: 32402162. PMCID: PMC7288982.

48. Park TY, Jeon J, Lee N, et al. 2023; Co-transplantation of autologous Treg cells in a cell therapy for Parkinson's disease. Nature. 619:606–615. DOI: 10.1038/s41586-023-06300-4. PMID: 37438521.

49. Wang YK, Zhu WW, Wu MH, et al. 2018; Human clinical-grade parthenogenetic ESC-derived dopaminergic neurons recover locomotive defects of nonhuman primate models of Parkinson's disease. Stem Cell Reports. 11:171–182. DOI: 10.1016/j.stemcr.2018.05.010. PMID: 29910127. PMCID: PMC6067059.

50. Piao J, Zabierowski S, Dubose BN, et al. 2021; Preclinical efficacy and safety of a human embryonic stem cell-derived midbrain dopamine progenitor product, MSK-DA01. Cell Stem Cell. 28:217–229.e7. DOI: 10.1016/j.stem.2021.01.004. PMID: 33545080. PMCID: PMC7903922.

51. Kirkeby A, Parmar M, Barker RA. 2017; Strategies for bringing stem cell-derived dopamine neurons to the clinic: a European approach (STEM-PD). Prog Brain Res. 230:165–190. DOI: 10.1016/bs.pbr.2016.11.011. PMID: 28552228.

52. Takahashi J. 2020; iPS cell-based therapy for Parkinson's disease: a Kyoto trial. Regen Ther. 13:18–22. DOI: 10.1016/j.reth.2020.06.002. PMID: 33490319. PMCID: PMC7794047.

53. Kirkeby A, Nelander J, Hoban DB, et al. 2023; Preclinical quality, safety, and efficacy of a human embryonic stem cell-derived product for the treatment of Parkinson's disease, STEM-PD. Cell Stem Cell. 30:1299–1314.e9. DOI: 10.1016/j.stem.2023.08.014. PMID: 37802036.

54. Hauser RA, Freeman TB, Snow BJ, et al. 1999; Long-term evaluation of bilateral fetal nigral transplantation in Parkinson disease. Arch Neurol. 56:179–187. DOI: 10.1001/archneur.56.2.179. PMID: 10025423.

55. Roy NS, Cleren C, Singh SK, Yang L, Beal MF, Goldman SA. 2006; Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat Med. 12:1259–1268. DOI: 10.1038/nm1495. PMID: 17057709.

56. Redmond DE Jr, Bjugstad KB, Teng YD, et al. 2007; Behavioral improvement in a primate Parkinson's model is associated with multiple homeostatic effects of human neural stem cells. Proc Natl Acad Sci U S A. 104:12175–12180. DOI: 10.1073/pnas.0704091104. PMID: 17586681. PMCID: PMC1896134.

57. Bachoud-Lévi AC, Gaura V, Brugières P, et al. 2006; Effect of fetal neural transplants in patients with Huntington's disease 6 years after surgery: a long-term follow-up study. Lancet Neurol. 5:303–309. DOI: 10.1016/S1474-4422(06)70381-7. PMID: 16545746.

58. Mendez I, Viñuela A, Astradsson A, et al. 2008; Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years. Nat Med. 14:507–509. DOI: 10.1038/nm1752. PMID: 18391961. PMCID: PMC2656682.

59. Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW. 2008; Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat Med. 14:504–506. DOI: 10.1038/nm1747. PMID: 18391962.

60. Li JY, Englund E, Holton JL, et al. 2008; Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med. 14:501–503. DOI: 10.1038/nm1746. PMID: 18391963.

61. Barker RA, Drouin-Ouellet J, Parmar M. 2015; Cell-based therapies for Parkinson disease-past insights and future potential. Nat Rev Neurol. 11:492–503. DOI: 10.1038/nrneurol.2015.123. PMID: 26240036.

62. Kikuchi T, Morizane A, Doi D, et al. 2017; Human iPS cell-derived dopaminergic neurons function in a primate Parkinson's disease model. Nature. 548:592–596. DOI: 10.1038/nature23664. PMID: 28858313.

63. Kyttälä A, Moraghebi R, Valensisi C, et al. 2016; Genetic variability overrides the impact of parental cell type and determines iPSC differentiation potential. Stem Cell Reports. 6:200–212. DOI: 10.1016/j.stemcr.2015.12.009. PMID: 26777058. PMCID: PMC4750096.

64. Singh VK, Kalsan M, Kumar N, Saini A, Chandra R. 2015; Induced pluripotent stem cells: applications in regenerative medicine, disease modeling, and drug discovery. Front Cell Dev Biol. 3:2. DOI: 10.3389/fcell.2015.00002. PMID: 25699255. PMCID: PMC4313779.

65. Allan LE, Petit GH, Brundin P. 2010; Cell transplantation in Parkinson's disease: problems and perspectives. Curr Opin Neurol. 23:426–432. DOI: 10.1097/WCO.0b013e32833b1f62. PMID: 20489615.

66. Kim TW, Koo SY, Studer L. 2020; Pluripotent stem cell therapies for Parkinson disease: present challenges and future opportunities. Front Cell Dev Biol. 8:729. DOI: 10.3389/fcell.2020.00729. PMID: 32903681. PMCID: PMC7438741.

67. Oricchio E, Papapetrou EP, Lafaille F, et al. 2014; A cell engineering strategy to enhance the safety of stem cell therapies. Cell Rep. 8:1677–1685. DOI: 10.1016/j.celrep.2014.08.039. PMID: 25242333. PMCID: PMC4177332.

68. Nishimura T, Xu H, Iwasaki M, et al. 2019; Sufficiency for inducible Caspase-9 safety switch in human pluripotent stem cells and disease cells. Gene Ther. 27:525–534. DOI: 10.1038/s41434-020-0179-z. PMID: 32704085.

69. Katsukawa M, Nakajima Y, Fukumoto A, Doi D, Takahashi J. 2016; Fail-safe therapy by gamma-ray irradiation against tumor formation by human-induced pluripotent stem cell-derived neural progenitors. Stem Cells Dev. 25:815–825. DOI: 10.1089/scd.2015.0394. PMID: 27059007.

70. Takagi Y, Takahashi J, Saiki H, et al. 2005; Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model. J Clin Invest. 115:102–109. DOI: 10.1172/JCI21137. PMID: 15630449. PMCID: PMC539189.

71. Morizane A, Kikuchi T, Hayashi T, et al. 2017; MHC matching improves engraftment of iPSC-derived neurons in non-human primates. Nat Commun. 8:385. DOI: 10.1038/s41467-017-00926-5. PMID: 28855509. PMCID: PMC5577234.

72. Parmar M. 2018; Towards stem cell based therapies for Parkinson's disease. Development. 145:dev156117. DOI: 10.1242/dev.156117. PMID: 29311261.

73. Volarevic V, Markovic BS, Gazdic M, et al. 2018; Ethical and safety issues of stem cell-based therapy. Int J Med Sci. 15:36–45. DOI: 10.7150/ijms.21666. PMID: 29333086. PMCID: PMC5765738.

74. Che YH, Lee H, Kim YJ. 2022; New insights into the epitranscriptomic control of pluripotent stem cell fate. Exp Mol Med. 54:1643–1651. DOI: 10.1038/s12276-022-00824-x. PMID: 36266446. PMCID: PMC9636187.

75. Lovell-Badge R, Anthony E, Barker RA, et al. 2021; ISSCR guidelines for stem cell research and clinical translation: the 2021 update. Stem Cell Reports. 16:1398–1408. DOI: 10.1016/j.stemcr.2021.05.012. PMID: 34048692. PMCID: PMC8190668.

76. Sullivan S, Stacey GN, Akazawa C, et al. 2018; Quality control guidelines for clinical-grade human induced pluripotent stem cell lines. Regen Med. 13:859–866. DOI: 10.2217/rme-2018-0095. PMID: 30205750.

77. Lee G, Papapetrou EP, Kim H, et al. 2009; Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature. 461:402–406. DOI: 10.1038/nature08320. PMID: 19693009. PMCID: PMC2784695.

78. Mukherjee-Clavin B, Mi R, Kern B, et al. 2019; Comparison of three congruent patient-specific cell types for the modelling of a human genetic Schwann-cell disorder. Nat Biomed Eng. 3:571–582. DOI: 10.1038/s41551-019-0381-8. PMID: 30962586. PMCID: PMC6612317.

79. Kim YJ, Lim H, Li Z, et al. 2014; Generation of multipotent induced neural crest by direct reprogramming of human postnatal fibroblasts with a single transcription factor. Cell Stem Cell. 15:497–506. DOI: 10.1016/j.stem.2014.07.013. PMID: 25158936.

80. Lee G, Ramirez CN, Kim H, et al. 2012; Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression. Nat Biotechnol. 30:1244–1248. DOI: 10.1038/nbt.2435. PMID: 23159879. PMCID: PMC3711177.

81. Choi IY, Lim HT, Che YH, Lee G, Kim YJ. 2021; Inhibition of the combinatorial signaling of transforming growth factor-beta and NOTCH promotes myotube formation of human pluripotent stem cell-derived skeletal muscle progenitor cells. Cells. 10:1649. DOI: 10.3390/cells10071649. PMID: 34209364. PMCID: PMC8303216.

82. Lee G, Studer L. 2011; Modelling familial dysautonomia in human induced pluripotent stem cells. Philos Trans R Soc Lond B Biol Sci. 366:2286–2296. DOI: 10.1098/rstb.2011.0026. PMID: 21727134. PMCID: PMC3130420.

83. Cooper O, Seo H, Andrabi S, et al. 2012; Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease. Sci Transl Med. 4:141ra90. DOI: 10.1126/scitranslmed.3003985.

84. Byers B, Cord B, Nguyen HN, et al. 2011; SNCA triplication Parkinson's patient's iPSC-derived DA neurons accumulate α-synuclein and are susceptible to oxidative stress. PLoS One. 6:e26159. DOI: 10.1371/journal.pone.0026159. PMID: 22110584. PMCID: PMC3217921.

85. Shulman JM, De Jager PL, Feany MB. 2011; Parkinson's disease: genetics and pathogenesis. Annu Rev Pathol. 6:193–222. DOI: 10.1146/annurev-pathol-011110-130242. PMID: 21034221.

86. Devine MJ, Ryten M, Vodicka P, et al. 2011; Parkinson's disease induced pluripotent stem cells with triplication of the α-synuclein locus. Nat Commun. 2:440. DOI: 10.1038/ncomms1453. PMID: 21863007. PMCID: PMC3265381.

87. Heman-Ackah SM, Manzano R, Hoozemans JJM, et al. 2017; Alpha-synuclein induces the unfolded protein response in Parkinson's disease SNCA triplication iPSC-derived neurons. Hum Mol Genet. 26:4441–4450. DOI: 10.1093/hmg/ddx331. PMID: 28973645. PMCID: PMC5886237.

88. Stojkovska I, Wani WY, Zunke F, et al. 2022; Rescue of α-synuclein aggregation in Parkinson's patient neurons by synergistic enhancement of ER proteostasis and protein trafficking. Neuron. 110:436–451.e11. DOI: 10.1016/j.neuron.2021.10.032. PMID: 34793693. PMCID: PMC8815333.

89. Prots I, Grosch J, Brazdis RM, et al. 2018; α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies. Proc Natl Acad Sci U S A. 115:7813–7818. DOI: 10.1073/pnas.1713129115. PMID: 29991596. PMCID: PMC6065020.

90. Ludtmann MHR, Angelova PR, Horrocks MH, et al. 2018; α-Synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson's disease. Nat Commun. 9:2293. DOI: 10.1038/s41467-018-04422-2. PMID: 29895861. PMCID: PMC5997668.

91. Diao X, Wang F, Becerra-Calixto A, Soto C, Mukherjee A. 2021; Induced pluripotent stem cell-derived dopaminergic neurons from familial Parkinson's disease patients display α-synuclein pathology and abnormal mitochondrial morphology. Cells. 10:2402. DOI: 10.3390/cells10092402. PMID: 34572052. PMCID: PMC8467069.

92. Zambon F, Cherubini M, Fernandes HJR, et al. 2019; Cellular α-synuclein pathology is associated with bioenergetic dysfunction in Parkinson's iPSC-derived dopamine neurons. Hum Mol Genet. 28:2001–2013. DOI: 10.1093/hmg/ddz038. PMID: 30753527. PMCID: PMC6548224.

93. Brazdis RM, Alecu JE, Marsch D, et al. 2020; Demonstration of brain region-specific neuronal vulnerability in human iPSC-based model of familial Parkinson's disease. Hum Mol Genet. 29:1180–1191. DOI: 10.1093/hmg/ddaa039. PMID: 32160287. PMCID: PMC7206857.

94. Chung CY, Khurana V, Auluck PK, et al. 2013; Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons. Science. 342:983–987. DOI: 10.1126/science.1245296. PMID: 24158904. PMCID: PMC4022187.

95. Ryan SD, Dolatabadi N, Chan SF, et al. 2013; Isogenic human iPSC Parkinson's model shows nitrosative stress-induced dysfunction in MEF2-PGC1α transcription. Cell. 155:1351–1364. DOI: 10.1016/j.cell.2013.11.009. PMID: 24290359. PMCID: PMC4028128.

96. Czaniecki C, Ryan T, Stykel MG, et al. 2019; Axonal pathology in hPSC-based models of Parkinson's disease results from loss of Nrf2 transcriptional activity at the Map1b gene locus. Proc Natl Acad Sci U S A. 116:14280–14289. DOI: 10.1073/pnas.1900576116. PMID: 31235589. PMCID: PMC6628831.

97. Ryan T, Bamm VV, Stykel MG, et al. 2018; Cardiolipin exposure on the outer mitochondrial membrane modulates α-synuclein. Nat Commun. 9:817. DOI: 10.1038/s41467-018-03241-9. PMID: 29483518. PMCID: PMC5827019.

98. Aflaki E, Borger DK, Moaven N, et al. 2016; A new glucocerebrosidase chaperone reduces α-synuclein and glycolipid levels in iPSC-derived dopaminergic neurons from patients with Gaucher disease and Parkinsonism. J Neurosci. 36:7441–7452. DOI: 10.1523/JNEUROSCI.0636-16.2016. PMID: 27413154. PMCID: PMC4945664.

99. Woodard CM, Campos BA, Kuo SH, et al. 2014; iPSC-derived dopamine neurons reveal differences between monozygotic twins discordant for Parkinson's disease. Cell Rep. 9:1173–1182. DOI: 10.1016/j.celrep.2014.10.023. PMID: 25456120. PMCID: PMC4255586.

100. Fernandes HJ, Hartfield EM, Christian HC, et al. 2016; ER stress and autophagic perturbations lead to elevated extracellular α-synuclein in GBA-N370S Parkinson's iPSC-derived dopamine neurons. Stem Cell Reports. 6:342–356. DOI: 10.1016/j.stemcr.2016.01.013. PMID: 26905200. PMCID: PMC4788783.

101. Schöndorf DC, Ivanyuk D, Baden P, et al. 2018; The NAD＋ precursor nicotinamide riboside rescues mitochondrial defects and neuronal loss in iPSC and fly models of Parkinson's disease. Cell Rep. 23:2976–2988. DOI: 10.1016/j.celrep.2018.05.009. PMID: 29874584.

102. Aboud AA, Tidball AM, Kumar KK, et al. 2012; Genetic risk for Parkinson's disease correlates with alterations in neuronal manganese sensitivity between two human subjects. Neurotoxicology. 33:1443–1449. DOI: 10.1016/j.neuro.2012.10.009. PMID: 23099318. PMCID: PMC3518601.

103. Jiang H, Ren Y, Yuen EY, et al. 2012; Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells. Nat Commun. 3:668. DOI: 10.1038/ncomms1669. PMID: 22314364. PMCID: PMC3498452.

104. Chung SY, Kishinevsky S, Mazzulli JR, et al. 2016; Parkin and PINK1 patient iPSC-derived midbrain dopamine neurons exhibit mitochondrial dysfunction and α-synuclein accumulation. Stem Cell Reports. 7:664–677. DOI: 10.1016/j.stemcr.2016.08.012. PMID: 27641647. PMCID: PMC5063469.

105. Oh CK, Sultan A, Platzer J, et al. 2017; S-nitrosylation of PINK1 attenuates PINK1/Parkin-dependent mitophagy in hiPSC-based Parkinson's disease models. Cell Rep. 21:2171–2182. DOI: 10.1016/j.celrep.2017.10.068. PMID: 29166608. PMCID: PMC5705204.

106. Seibler P, Graziotto J, Jeong H, Simunovic F, Klein C, Krainc D. 2011; Mitochondrial Parkin recruitment is impaired in neurons derived from mutant PINK1 induced pluripotent stem cells. J Neurosci. 31:5970–5976. DOI: 10.1523/JNEUROSCI.4441-10.2011. PMID: 21508222. PMCID: PMC3091622.

107. Nguyen HN, Byers B, Cord B, et al. 2011; LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell. 8:267–280. DOI: 10.1016/j.stem.2011.01.013. PMID: 21362567. PMCID: PMC3578553.

108. Sánchez-Danés A, Richaud-Patin Y, Carballo-Carbajal I, et al. 2012; Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease. EMBO Mol Med. 4:380–395. DOI: 10.1002/emmm.201200215. PMID: 22407749. PMCID: PMC3403296.

109. Boecker CA, Goldsmith J, Dou D, Cajka GG, Holzbaur ELF. 2021; Increased LRRK2 kinase activity alters neuronal autophagy by disrupting the axonal transport of autophagosomes. Curr Biol. 31:2140–2154.e6. DOI: 10.1016/j.cub.2021.02.061. PMID: 33765413. PMCID: PMC8154747.

110. Hsieh CH, Shaltouki A, Gonzalez AE, et al. 2016; Functional impairment in miro degradation and mitophagy is a shared feature in familial and sporadic Parkinson's disease. Cell Stem Cell. 19:709–724. DOI: 10.1016/j.stem.2016.08.002. PMID: 27618216. PMCID: PMC5135570.

111. Orenstein SJ, Kuo SH, Tasset I, et al. 2013; Interplay of LRRK2 with chaperone-mediated autophagy. Nat Neurosci. 16:394–406. DOI: 10.1038/nn.3350. PMID: 23455607. PMCID: PMC3609872.

112. Sanders LH, Laganière J, Cooper O, et al. 2014; LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson's disease patients: reversal by gene correction. Neurobiol Dis. 62:381–386. DOI: 10.1016/j.nbd.2013.10.013. PMID: 24148854. PMCID: PMC3877733.

113. Sheng ZH, Cai Q. 2012; Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration. Nat Rev Neurosci. 13:77–93. DOI: 10.1038/nrn3156. PMID: 22218207. PMCID: PMC4962561.

114. Schwab AJ, Sison SL, Meade MR, Broniowska KA, Corbett JA, Ebert AD. 2017; Decreased sirtuin deacetylase activity in LRRK2 G2019S iPSC-derived dopaminergic neurons. Stem Cell Reports. 9:1839–1852. DOI: 10.1016/j.stemcr.2017.10.010. PMID: 29129681. PMCID: PMC5785678.

115. Korecka JA, Talbot S, Osborn TM, et al. 2019; Neurite collapse and altered ER Ca2^＋ control in human Parkinson disease patient iPSC-derived neurons with LRRK2 G2019S mutation. Stem Cell Reports. 12:29–41. DOI: 10.1016/j.stemcr.2018.11.021. PMID: 30595548. PMCID: PMC6335600.

116. Gonzalez-Cano L, Menzl I, Tisserand J, Nicklas S, Schwamborn JC. 2018; Parkinson's disease-associated mutant LRRK2-mediated inhibition of miRNA activity is antagonized by TRIM32. Mol Neurobiol. 55:3490–3498. DOI: 10.1007/s12035-017-0570-y. PMID: 28508149. PMCID: PMC5842508.

117. Bono K, Hara-Miyauchi C, Sumi S, Oka H, Iguchi Y, Okano HJ. 2020; Endosomal dysfunction in iPSC-derived neural cells from Parkinson's disease patients with VPS35 D620N. Mol Brain. 13:137. DOI: 10.1186/s13041-020-00675-5. PMID: 33032646. PMCID: PMC7542911.

118. Cookson MR. 2010; The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nat Rev Neurosci. 11:791–797. DOI: 10.1038/nrn2935. PMID: 21088684. PMCID: PMC4662256.

119. Liu GH, Qu J, Suzuki K, et al. 2012; Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature. 491:603–607. DOI: 10.1038/nature11557. PMID: 23075850. PMCID: PMC3504651.

120. Reinhardt P, Schmid B, Burbulla LF, et al. 2013; Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression. Cell Stem Cell. 12:354–367. DOI: 10.1016/j.stem.2013.01.008. PMID: 23472874.

121. Tabata Y, Imaizumi Y, Sugawara M, et al. 2018; T-type calcium channels determine the vulnerability of dopaminergic neurons to mitochondrial stress in familial Parkinson disease. Stem Cell Reports. 11:1171–1184. DOI: 10.1016/j.stemcr.2018.09.006. PMID: 30344006. PMCID: PMC6234903.

122. Burbulla LF, Jeon S, Zheng J, Song P, Silverman RB, Krainc D. 2019; A modulator of wild-type glucocerebrosidase improves pathogenic phenotypes in dopaminergic neuronal models of Parkinson's disease. Sci Transl Med. 11:eaau6870. DOI: 10.1126/scitranslmed.aau6870. PMID: 31619543. PMCID: PMC7359409.

123. de Lau LM, Breteler MM. 2006; Epidemiology of Parkinson's disease. Lancet Neurol. 5:525–535. DOI: 10.1016/S1474-4422(06)70471-9. PMID: 16713924.

124. Munsie LN, Milnerwood AJ, Seibler P, et al. 2015; Retromer-dependent neurotransmitter receptor trafficking to synapses is altered by the Parkinson's disease VPS35 mutation p.D620N. Hum Mol Genet. 24:1691–1703. DOI: 10.1093/hmg/ddu582. PMID: 25416282.

125. Hirano K, Fujimaki M, Sasazawa Y, et al. 2019; Neuroprotective effects of memantine via enhancement of autophagy. Biochem Biophys Res Commun. 518:161–170. DOI: 10.1016/j.bbrc.2019.08.025. PMID: 31431260.

126. Fernández-Santiago R, Carballo-Carbajal I, Castellano G, et al. 2015; Aberrant epigenome in iPSC-derived dopaminergic neurons from Parkinson's disease patients. EMBO Mol Med. 7:1529–1546. DOI: 10.15252/emmm.201505439. PMID: 26516212. PMCID: PMC4693505.

127. Laperle AH, Sances S, Yucer N, et al. 2020; iPSC modeling of young-onset Parkinson's disease reveals a molecular signature of disease and novel therapeutic candidates. Nat Med. 26:289–299. DOI: 10.1038/s41591-019-0739-1. PMID: 31988461.

128. Burbulla LF, Song P, Mazzulli JR, et al. 2017; Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease. Science. 357:1255–1261. DOI: 10.1126/science.aam9080. PMID: 28882997. PMCID: PMC6021018.

129. Kouroupi G, Taoufik E, Vlachos IS, et al. 2017; Defective synaptic connectivity and axonal neuropathology in a human iPSC-based model of familial Parkinson's disease. Proc Natl Acad Sci U S A. 114:E3679–E3688. DOI: 10.1073/pnas.1617259114. PMID: 28416701. PMCID: PMC5422768.

130. Fanning S, Haque A, Imberdis T, et al. 2019; Lipidomic analysis of α-synuclein neurotoxicity identifies stearoyl CoA desaturase as a target for Parkinson treatment. Mol Cell. 73:1001–1014.e8. DOI: 10.1016/j.molcel.2018.11.028. PMID: 30527540. PMCID: PMC6408259.

131. Gandelman M, Dansithong W, Kales SC, et al. 2021; The AKT modulator A-443654 reduces α-synuclein expression and normalizes ER stress and autophagy. J Biol Chem. 297:101191. DOI: 10.1016/j.jbc.2021.101191. PMID: 34520759. PMCID: PMC8482485.

132. Ho GPH, Ramalingam N, Imberdis T, Wilkie EC, Dettmer U, Selkoe DJ. 2021; Upregulation of cellular palmitoylation mitigates α-synuclein accumulation and neurotoxicity. Mov Disord. 36:348–359. DOI: 10.1002/mds.28346. PMID: 33103814. PMCID: PMC8887921.

133. Lin M, Mackie PM, Shaerzadeh F, et al. 2021; In Parkinson's patient-derived dopamine neurons, the triplication of α-synuclein locus induces distinctive firing pattern by impeding D2 receptor autoinhibition. Acta Neuropathol Commun. 9:107. DOI: 10.1186/s40478-021-01203-9. PMID: 34099060. PMCID: PMC8185945.

134. Mazzulli JR, Zunke F, Tsunemi T, et al. 2016; Activation of β-glucocerebrosidase reduces pathological α-synuclein and restores lysosomal function in Parkinson's patient midbrain neurons. J Neurosci. 36:7693–7706. DOI: 10.1523/JNEUROSCI.0628-16.2016. PMID: 27445146. PMCID: PMC4951575.

135. Burbulla LF, Zheng J, Song P, et al. 2021; Direct targeting of wild-type glucocerebrosidase by antipsychotic quetiapine improves pathogenic phenotypes in Parkinson's disease models. JCI Insight. 6:e148649. DOI: 10.1172/jci.insight.148649. PMID: 34622801. PMCID: PMC8525588.

136. Ren Y, Jiang H, Hu Z, et al. 2015; Parkin mutations reduce the complexity of neuronal processes in iPSC-derived human neurons. Stem Cells. 33:68–78. DOI: 10.1002/stem.1854. PMID: 25332110. PMCID: PMC4429885.

137. Yamaguchi A, Ishikawa KI, Inoshita T, et al. 2020; Identifying therapeutic agents for amelioration of mitochondrial clearance disorder in neurons of familial Parkinson disease. Stem Cell Reports. 14:1060–1075. DOI: 10.1016/j.stemcr.2020.04.011. PMID: 32470327. PMCID: PMC7355139.

138. Panagiotakopoulou V, Ivanyuk D, De Cicco S, et al. 2020; Interferon-γ signaling synergizes with LRRK2 in neurons and microglia derived from human induced pluripotent stem cells. Nat Commun. 11:5163. DOI: 10.1038/s41467-020-18755-4. PMID: 33057020. PMCID: PMC7560616.

139. Ke M, Chong CM, Zeng H, et al. 2020; Azoramide protects iPSC-derived dopaminergic neurons with PLA2G6 D331Y mutation through restoring ER function and CREB signaling. Cell Death Dis. 11:130. DOI: 10.1038/s41419-020-2312-8. PMID: 32071291. PMCID: PMC7028918.

140. Yun W, Kim YJ, Lee G. 2022; Direct conversion to achieve glial cell fates: oligodendrocytes and Schwann cells. Int J Stem Cells. 15:14–25. DOI: 10.15283/ijsc22008. PMID: 35220289. PMCID: PMC8889328.

141. Kwak TH, Kang JH, Hali S, et al. 2020; Generation of homogeneous midbrain organoids with in vivo-like cellular composition facilitates neurotoxin-based Parkinson's disease modeling. Stem Cells. 38:727–740. DOI: 10.1002/stem.3163. PMID: 32083763.

142. Becerra-Calixto A, Mukherjee A, Ramirez S, et al. 2023; Lewy body-like pathology and loss of dopaminergic neurons in midbrain organoids derived from familial Parkinson's disease Patient. Cells. 12:625. DOI: 10.3390/cells12040625. PMID: 36831291. PMCID: PMC9954141.

143. Ke M, Chong CM, Zhu Q, et al. 2021; Comprehensive perspectives on experimental models for Parkinson's disease. Aging Dis. 12:223–246. DOI: 10.14336/AD.2020.0331. PMID: 33532138. PMCID: PMC7801282.

144. Pons-Espinal M, Blasco-Agell L, Consiglio A. 2021; Dissecting the non-neuronal cell contribution to Parkinson's disease pathogenesis using induced pluripotent stem cells. Cell Mol Life Sci. 78:2081–2094. DOI: 10.1007/s00018-020-03700-x. PMID: 33210214. PMCID: PMC7966189.

145. Kim T, Song JJ, Puspita L, Valiulahi P, Shim JW, Lee SH. 2017; In vitro generation of mature midbrain-type dopamine neurons by adjusting exogenous Nurr1 and Foxa2 expressions to their physiologic patterns. Exp Mol Med. 49:e300. DOI: 10.1038/emm.2016.163. PMID: 28280264. PMCID: PMC5382556.

146. Nolbrant S, Heuer A, Parmar M, Kirkeby A. 2017; Generation of high-purity human ventral midbrain dopaminergic progenitors for in vitro maturation and intracerebral transplantation. Nat Protoc. 12:1962–1979. DOI: 10.1038/nprot.2017.078. PMID: 28858290.

147. Han JJ. 2023; FDA Modernization Act 2.0 allows for alternatives to animal testing. Artif Organs. 47:449–450. DOI: 10.1111/aor.14503. PMID: 36762462.

148. Wadman M. 2023; FDA no longer has to require animal testing for new drugs. Science. 379:127–128. DOI: 10.1126/science.adg6276. PMID: 36634170.

149. Cornacchia D, Studer L. 2017; Back and forth in time: directing age in iPSC-derived lineages. Brain Res. 1656:14–26. DOI: 10.1016/j.brainres.2015.11.013. PMID: 26592774. PMCID: PMC4870156.

150. Liu GH, Ding Z, Izpisua Belmonte JC. 2012; iPSC technology to study human aging and aging-related disorders. Curr Opin Cell Biol. 24:765–774. DOI: 10.1016/j.ceb.2012.08.014. PMID: 22999273.

151. Miller JD, Ganat YM, Kishinevsky S, et al. 2013; Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell. 13:691–705. DOI: 10.1016/j.stem.2013.11.006. PMID: 24315443. PMCID: PMC4153390.

152. Luk KC, Song C, O'Brien P, et al. 2009; Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc Natl Acad Sci U S A. 106:20051–20056. DOI: 10.1073/pnas.0908005106. PMID: 19892735. PMCID: PMC2785290.

153. Kim MS, Ra EA, Kweon SH, et al. 2023; Advanced human iPSC-based preclinical model for Parkinson's disease with optogenetic alpha-synuclein aggregation. Cell Stem Cell. 30:973–986.e11. DOI: 10.1016/j.stem.2023.05.015. PMID: 37339636. PMCID: PMC10829432.

154. Ra EA, Kim MS, Lee G. 2023; Optogenetic induction of alpha-synuclein aggregation in human dopaminergic neurons to model Parkinson's disease pathology. STAR Protoc. 4:102609. DOI: 10.1016/j.xpro.2023.102609. PMID: 37742181. PMCID: PMC10522986.

155. Chandra R, Sokratian A, Chavez KR, et al. 2023; Gut mucosal cells transfer α-synuclein to the vagus nerve. JCI Insight. 8:e172192. DOI: 10.1172/jci.insight.172192. PMID: 38063197. PMCID: PMC10795834.

156. Kim S, Kwon SH, Kam TI, et al. 2019; Transneuronal propagation of pathologic α-synuclein from the gut to the brain models Parkinson's disease. Neuron. 103:627–641.e7. DOI: 10.1016/j.neuron.2019.05.035. PMID: 31255487. PMCID: PMC6706297.

157. Ettle B, Kuhbandner K, Jörg S, Hoffmann A, Winkler J, Linker RA. 2016; α-Synuclein deficiency promotes neuroinflammation by increasing Th1 cell-mediated immune responses. J Neuroinflammation. 13:201. DOI: 10.1186/s12974-016-0694-4. PMID: 27565429. PMCID: PMC5002168.

158. Desplats P, Lee HJ, Bae EJ, et al. 2009; Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci U S A. 106:13010–13015. DOI: 10.1073/pnas.0903691106. PMID: 19651612. PMCID: PMC2722313.

159. Magistrelli L, Contaldi E, Comi C. 2021; The impact of SNCA variations and its product alpha-synuclein on non-motor features of Parkinson's disease. Life (Basel). 11:804. DOI: 10.3390/life11080804. PMID: 34440548. PMCID: PMC8401994.

160. Siddiqui IJ, Pervaiz N, Abbasi AA. 2016; The Parkinson disease gene SNCA: evolutionary and structural insights with pathological implication. Sci Rep. 6:24475. DOI: 10.1038/srep24475. PMID: 27080380. PMCID: PMC4832246.

161. Hallacli E, Kayatekin C, Nazeen S, et al. 2022; The Parkinson's disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability. Cell. 185:2035–2056.e33. DOI: 10.1016/j.cell.2022.05.008. PMID: 35688132. PMCID: PMC9394447.

162. Mullin S, Schapira A. 2013; α-Synuclein and mitochondrial dysfunction in Parkinson's disease. Mol Neurobiol. 47:587–597. DOI: 10.1007/s12035-013-8394-x. PMID: 23361255. PMCID: PMC4199090.

163. Mazzulli JR, Zunke F, Isacson O, Studer L, Krainc D. 2016; α-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models. Proc Natl Acad Sci U S A. 113:1931–1936. DOI: 10.1073/pnas.1520335113. PMID: 26839413. PMCID: PMC4763774.

164. Fonseca-Ornelas L, Viennet T, Rovere M, et al. 2021; Altered conformation of α-synuclein drives dysfunction of synaptic vesicles in a synaptosomal model of Parkinson's disease. Cell Rep. 36:109333. DOI: 10.1016/j.celrep.2021.109333. PMID: 34233191. PMCID: PMC8552450.

165. Kurapati S, Sadaoka T, Rajbhandari L, et al. 2017; Role of the JNK pathway in varicella-zoster virus lytic infection and reactivation. J Virol. 91:e00640–e00617. DOI: 10.1128/JVI.00640-17. PMID: 28637759. PMCID: PMC5553188.

166. Che YH, Choi IY, Song CE, et al. 2023; Peripheral neuron-organoid interaction induces colonic epithelial differentiation via non-synaptic substance P secretion. Int J Stem Cells. 16:269–280. DOI: 10.15283/ijsc23026. PMID: 37385635. PMCID: PMC10465334.

167. Susaimanickam PJ, Kiral FR, Park IH. 2022; Region specific brain organoids to study neurodevelopmental disorders. Int J Stem Cells. 15:26–40. DOI: 10.15283/ijsc22006. PMID: 35220290. PMCID: PMC8889336.

168. Jang H, Kim SH, Koh Y, Yoon KJ. 2022; Engineering brain organoids: toward mature neural circuitry with an intact cytoar-chitecture. Int J Stem Cells. 15:41–59. DOI: 10.15283/ijsc22004. PMID: 35220291. PMCID: PMC8889333.