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Using Patient-Derived Induced Pluripotent Stem Cells to Identify Parkinson’s Disease-Relevant Phenotypes

  • S. L. Sison
  • S. C. Vermilyea
  • M. E. Emborg
  • A. D. Ebert
Genetics (V Bonifati, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Genetics

Abstract

Purpose of Review

Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting older individuals. The specific cause underlying dopaminergic (DA) neuron loss in the substantia nigra, a pathological hallmark of PD, remains elusive. Here, we highlight peer-reviewed reports using induced pluripotent stem cells (iPSCs) to model PD in vitro and discuss the potential disease-relevant phenotypes that may lead to a better understanding of PD etiology. Benefits of iPSCs are that they retain the genetic background of the donor individual and can be differentiated into specialized neurons to facilitate disease modeling.

Recent Findings

Mitochondrial dysfunction, oxidative stress, ER stress, and alpha-synuclein accumulation are common phenotypes observed in PD iPSC-derived neurons. New culturing technologies, such as directed reprogramming and midbrain organoids, offer innovative ways of investigating intraneuronal mechanisms of PD pathology.

Summary

PD patient-derived iPSCs are an evolving resource to understand PD pathology and identify therapeutic targets.

Keywords

Mitochondria Oxidative stress Dopaminergic neurons Alpha synuclein LRRK2 Gene editing 

Notes

Funding information

This work is supported by NIH grants R24OD019803 (M.E.E.), P51OD011106 (M.E.E.), NINDS T32-Neuroscience Training Program (S.C.V.), the UW-Madison Office of the Vice Chancellor for Research and Graduate Education (M.E.E.), Advancing a Healthier Wisconsin (A.D.E.), and philanthropic support to the Medical College of Wisconsin for Parkinson’s disease research (A.D.E.).

Compliance with Ethical Standards

Conflict of Interest

Allison D. Ebert, Marina Emborg, Samantha Sison and Scott Vermilyea each declare no potential conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Marras C, Beck JC, Bower JH, et al. Prevalence of Parkinson’s disease across North America. NPJ Parkinsons Dis. 2018;4:21.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Karimi-Moghadam A, Charsouei S, Bell B, Jabalameli MR. Parkinson disease from Mendelian forms to genetic susceptibility: new molecular insights into the neurodegeneration process. Cell Mol Neurobiol. 2018;38(6):1153–78.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Zanon A, Pramstaller PP, Hicks AA, Pichler I. Environmental and genetic variables influencing mitochondrial health and Parkinson’s disease penetrance. Park Dis. 2018;2018:8684906.Google Scholar
  4. 4.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.PubMedCrossRefGoogle Scholar
  5. 5.
    Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(5858):1917–20.PubMedCrossRefGoogle Scholar
  6. 6.
    Jiang H, Ren Y, Yuen EY, Zhong P, Ghaedi M, Hu Z, et al. Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells. Nat Commun. 2012;3:668.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Kouroupi G, Taoufik E, Vlachos IS, Tsioras K, Antoniou N, Papastefanaki F, et al. Defective synaptic connectivity and axonal neuropathology in a human iPSC-based model of familial Parkinson’s disease. Proc Natl Acad Sci U S A. 2017;114(18):E3679–E88.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Ohta E, Nihira T, Uchino A, Imaizumi Y, Okada Y, Akamatsu W, et al. I2020T mutant LRRK2 iPSC-derived neurons in the Sagamihara family exhibit increased tau phosphorylation through the AKT/GSK-3beta signaling pathway. Hum Mol Genet. 2015;24(17):4879–900.PubMedCrossRefGoogle Scholar
  9. 9.
    Schwab AJ, Ebert AD. Neurite aggregation and calcium dysfunction in iPSC-derived sensory neurons with Parkinson’s disease-related LRRK2 G2019S mutation. Stem Cell Reports. 2015;5(6):1039–52.4682343.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Hu Z, Pu J, Jiang H, Zhong P, Qiu J, Li F, et al. Generation of Naivetropic induced pluripotent stem cells from Parkinson’s disease patients for high-efficiency genetic manipulation and disease modeling. Stem Cells Dev. 2015;24(21):2591–604.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD. Mitochondrial complex I deficiency in Parkinson's disease. Lancet. 1989;1(8649):1269.PubMedCrossRefGoogle Scholar
  12. 12.
    Navarro A, Boveris A, Bandez MJ, et al. Human brain cortex: mitochondrial oxidative damage and adaptive response in Parkinson disease and in dementia with Lewy bodies. Free Radic Biol Med. 2009;46(12):1574–80.PubMedCrossRefGoogle Scholar
  13. 13.
    Keeney PM, Xie J, Capaldi RA, Bennett JP Jr. Parkinson’s disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled. J Neurosci. 2006;26(19):5256–64.PubMedCrossRefGoogle Scholar
  14. 14.
    Parker WD Jr, Parks JK, Swerdlow RH. Complex I deficiency in Parkinson’s disease frontal cortex. Brain Res. 2008;1189:215–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Ferrer I, Perez E, Dalfo E, Barrachina M. Abnormal levels of prohibitin and ATP synthase in the substantia nigra and frontal cortex in Parkinson’s disease. Neurosci Lett. 2007;415(3):205–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Chu Y, Goldman JG, Kelly L, He Y, Waliczek T, Kordower JH. Abnormal alpha-synuclein reduces nigral voltage-dependent anion channel 1 in sporadic and experimental Parkinson’s disease. Neurobiol Dis. 2014;69:1–14.PubMedCrossRefGoogle Scholar
  17. 17.
    Bender A, Desplats P, Spencer B, et al. TOM40 mediates mitochondrial dysfunction induced by alpha-synuclein accumulation in Parkinson’s disease. PLoS One. 2013;8(4):e62277.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Dunn L, Allen GF, Mamais A, et al. Dysregulation of glucose metabolism is an early event in sporadic Parkinson’s disease. Neurobiol Aging. 2014;35(5):1111–5.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Surmeier DJ. Determinants of dopaminergic neuron loss in Parkinson's disease. FEBS J. 2018.Google Scholar
  20. 20.
    Fernandes HJR, Hartfield EM, Christian HC, Emmanoulidou E, Zheng Y, Booth H, et al. ER stress and autophagic perturbations lead to elevated extracellular α-synuclein in GBA-N370S Parkinson’s iPSC-derived dopamine neurons. Stem Cell Reports. 2016;6(3):342–56.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    • Kim S, Yun SP, Lee S, et al. GBA1 deficiency negatively affects physiological alpha-synuclein tetramers and related multimers. Proc Natl Acad Sci U S A. 2018;115(4):798–803 Consistent with the findings from Dettmer et al 2015, this study shows that the pathogenic L444P GBA1 mutation destablizes α-synuclein protein generating more pathological monomeric α-synuclein protein. PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    •• Schondorf DC, Ivanyuk D, Baden P, et al. The NAD+ precursor nicotinamide riboside rescues mitochondrial defects and neuronal loss in iPSC and Fly Models of Parkinson’s disease. Cell Rep. 2018;23(10):2976–88 This study reports mitochondrial dysfunction and ER stress in GBA patient iPSC-derived DA neurons and identifies alterations in NAD+ metabolism. Together with Schwab et al 2017, these papers identify potential mechanisms underlying the mitochondrial defects in PD DA neurons. PubMedCrossRefGoogle Scholar
  23. 23.
    Nguyen HN, Byers B, Cord B, Shcheglovitov A, Byrne J, Gujar P, et al. LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell. 2011;8(3):267–80.3578553.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Cooper O, Seo H, Andrabi S, et al. Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson’s disease. Sci Transl Med. 2012;4(141):141ra90.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Sanchez-Danes A, Richaud-Patin Y, Carballo-Carbajal I, et al. Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease. EMBO Mol Med. 2012;4(5):380–95.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Reinhardt P, Schmid B, Burbulla LF, Schöndorf DC, Wagner L, Glatza M, et al. Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression. Cell Stem Cell. 2013;12(3):354–67.PubMedCrossRefGoogle Scholar
  27. 27.
    Su YC, Qi X. Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation. Hum Mol Genet. 2013;22(22):4545–61.PubMedCrossRefGoogle Scholar
  28. 28.
    Sanders LH, Laganiere J, Cooper O, et al. LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson's disease patients: reversal by gene correction. Neurobiol Dis. 2014;62:381–6.3877733.PubMedCrossRefGoogle Scholar
  29. 29.
    Hsieh CH, Shaltouki A, Gonzalez AE, et al. Functional impairment in miro degradation and mitophagy Is a shared feature in familial and sporadic Parkinson’s disease. Cell Stem Cell. 2016;19(6):709–24.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    •• Lin L, Göke J, Cukuroglu E, Dranias MR, VanDongen AM, Stanton LW. Molecular features underlying neurodegeneration identified through in vitro modeling of genetically diverse Parkinson’s disease patients. Cell Reports. 2016;15(11):2411–26 This paper reports increased levels of phosphorylated α-synuclein protein, increased susceptibility to neurotoxins, and gene dysregulation in DA neurons across multiple different PD genotypes suggesting potentially shared disease processes. PubMedCrossRefGoogle Scholar
  31. 31.
    Khurana V, Peng J, Chung CY, et al. Genome-scale networks link neurodegenerative disease genes to α;- synuclein through specific molecular pathways. Cell Syst. 2017;4(2):157–70.e14.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    •• Schwab AJ, Sison SL, Meade MR, Broniowska KA, Corbett JA, Ebert AD. Decreased sirtuin deacetylase activity in LRRK2 G2019S iPSC-derived dopaminergic neurons. Stem Cell Reports. 2017;9(6):1839–52 This study analyzes three different iPSC-derived neuronal subtypes from LRRK2 G2019S PD patients and reports mitochondrial defects specific to DA neurons, including decreased NAD+ levels and sirtuin activity. Together with Schondorf et al 2018, these papers identify potential mechanisms underlying the mitochondrial defects in PD DA neurons. PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Qing X, Walter J, Jarazo J, Arias-Fuenzalida J, Hillje A-L, Schwamborn JC. CRISPR/Cas9 and piggyBac-mediated footprint-free LRRK2-G2019S knock-in reveals neuronal complexity phenotypes and α-Synuclein modulation in dopaminergic neurons. Stem Cell Res. 2017;24:44–50.PubMedCrossRefGoogle Scholar
  34. 34.
    Iannielli A, Bido S, Folladori L, Segnali A, Cancellieri C, Maresca A, et al. Pharmacological inhibition of necroptosis protects from dopaminergic neuronal cell death in Parkinson’s disease models. Cell Rep. 2018;22(8):2066–79.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Imaizumi Y, Okada Y, Akamatsu W, Koike M, Kuzumaki N, Hayakawa H, et al. Mitochondrial dysfunction associated with increased oxidative stress and α-synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue. Mol Brain. 2012;5(1):35.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Miller JD, Ganat YM, Kishinevsky S, Bowman RL, Liu B, Tu EY, et al. Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell. 2013;13(6):691–705.4153390.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Shaltouki A, Sivapatham R, Pei Y, Gerencser AA, Momčilović O, Rao MS, et al. Mitochondrial alterations by PARKIN in dopaminergic neurons using PARK2 patient-specific and PARK2 knockout isogenic iPSC lines. Stem Cell Rep. 2015;4(5):847–59.CrossRefGoogle Scholar
  38. 38.
    •• Chung SY, Kishinevsky S, Mazzulli JR, et al. Parkin and PINK1 Patient iPSC-derived midbrain dopamine neurons exhibit mitochondrial dysfunction and a-synuclein accumulation. Stem Cell Reports. 2016;7(4):664–77 This paper reports abnormal insoluble α-synuclein protein and co-expression with ubiquitin in PARKIN and PINK1 iPSC-derived DA neurons indicating that the iPSC model can recapitulate a small component of Lewy body pathology. They also show that the DA neuron differentiation protocol impacts the phenotypes observed. PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Vera E, Bosco N, Studer L. Generating late-onset human iPSC-based disease models by inducing neuronal age-related phenotypes through telomerase manipulation. Cell Rep. 2016;17(4):1184–92.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Shiba-Fukushima K, Ishikawa K-I, Inoshita T, et al. Evidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson’s disease. Hum Mol Genet. 2017;26(16):3172–85.PubMedGoogle Scholar
  41. 41.
    Suzuki S, Akamatsu W, Kisa F, Sone T, Ishikawa KI, Kuzumaki N, et al. Efficient induction of dopaminergic neuron differentiation from induced pluripotent stem cells reveals impaired mitophagy in PARK2 neurons. Biochem Biophys Res Commun. 2017;483(1):88–93.PubMedCrossRefGoogle Scholar
  42. 42.
    Zanon A, Kalvakuri S, Rakovic A, Foco L, Guida M, Schwienbacher C, et al. SLP-2 interacts with Parkin in mitochondria and prevents mitochondrial dysfunction in Parkin-deficient human iPSC-derived neurons and drosophila. Hum Mol Genet. 2017;26(13):2412–25.PubMedCrossRefGoogle Scholar
  43. 43.
    Cartelli D, Amadeo A, Calogero AM, Casagrande FVM, de Gregorio C, Gioria M, et al. Parkin absence accelerates microtubule aging in dopaminergic neurons. Neurobiol Aging. 2018;61:66–74.PubMedCrossRefGoogle Scholar
  44. 44.
    Azkona G, López de Maturana R, del Rio P, et al. LRRK2 expression is deregulated in fibroblasts and neurons from Parkinson patients with mutations in PINK1. Mol Neurobiol. 2018;55(1):506–16.PubMedCrossRefGoogle Scholar
  45. 45.
    Chung CY, Khurana V, Auluck PK, Tardiff DF, Mazzulli JR, Soldner F, et al. Identification and rescue of α-synuclein toxicity in Parkinson patient–derived neurons. Science. 2013;342(6161):983–7.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    • Dettmer U, Newman AJ, Soldner F, et al. Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nature Commun. 2015;6:7314 This study shows that pathogenic α-synuclein mutations in PD iPSC-derived DA neurons reduces α-synuclein protein tetramer formation in favor of the monomer confirmation, which may initiate α-synuclein pathogenesis. CrossRefGoogle Scholar
  47. 47.
    Little D, Luft C, Mosaku O, Lorvellec M, Yao Z, Paillusson S, et al. A single cell high content assay detects mitochondrial dysfunction in iPSC-derived neurons with mutations in SNCA. Sci Rep. 2018;8(1):9033.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Byers B, Cord B, Nguyen HN, Schüle B, Fenno L, Lee PC, et al. SNCA triplication Parkinson’s patient’s iPSC-derived DA neurons accumulate α-synuclein and are susceptible to oxidative stress. PLoS One. 2011;6(11):e26159.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Heman-Ackah SM, Manzano R, Hoozemans JJM, Scheper W, Flynn R, Haerty W, et al. Alpha-synuclein induces the unfolded protein response in Parkinson’s disease SNCA triplication iPSC-derived neurons. Hum Mol Genet. 2017;26(22):4441–50.PubMedCrossRefGoogle Scholar
  50. 50.
    • Ludtmann MHR, Angelova PR, Horrocks MH, et al. α-Synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson’s disease. Nature Commun. 2018;9(1):2293 This study reports increased aggregated α-synuclein protein and increased redox index in SNCA triplication iPSC-derived cortical neurons that is normalized after CRISPR repair. CrossRefGoogle Scholar
  51. 51.
    Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet. 2006;38(5):515–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Taanman JW. The mitochondrial genome: structure, transcription, translation and replication. Biochim Biophys Acta. 1999;1410(2):103–23.PubMedCrossRefGoogle Scholar
  53. 53.
    Bindoff LA, Birch-Machin MA, Cartlidge NE, Parker WD Jr, Turnbull DM. Respiratory chain abnormalities in skeletal muscle from patients with Parkinson’s disease. J Neurol Sci. 1991;104(2):203–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Krige D, Carroll MT, Cooper JM, Marsden CD, Schapira AH. Platelet mitochondrial function in Parkinson's disease. The Royal Kings and Queens Parkinson disease research group. Ann Neurol. 1992;32(6):782–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Parker WD Jr, Boyson SJ, Parks JK. Abnormalities of the electron transport chain in idiopathic Parkinson’s disease. Ann Neurol. 1989;26(6):719–23.PubMedCrossRefGoogle Scholar
  56. 56.
    Toulorge D, Schapira AHV, Hajj R. Molecular changes in the postmortem parkinsonian brain. J Neurochem. 2016;139(S1):27–58.PubMedCrossRefGoogle Scholar
  57. 57.
    Yoritaka A, Hattori N, Uchida K, Tanaka M, Stadtman ER, Mizuno Y. Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. Proc Natl Acad Sci U S A. 1996;93(7):2696–701.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Alam ZI, Daniel SE, Lees AJ, Marsden DC, Jenner P, Halliwell B. A generalised increase in protein carbonyls in the brain in Parkinson’s but not incidental Lewy body disease. J Neurochem. 1997;69(3):1326–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Mythri RB, Venkateshappa C, Harish G, Mahadevan A, Muthane UB, Yasha TC, et al. Evaluation of markers of oxidative stress, antioxidant function and astrocytic proliferation in the striatum and frontal cortex of Parkinson’s disease brains. Neurochem Res. 2011;36(8):1452–63.PubMedCrossRefGoogle Scholar
  60. 60.
    Shimura-Miura H, Hattori N, Kang D, Miyako K, Nakabeppu Y, Mizuno Y. Increased 8-oxo-dGTPase in the mitochondria of substantia nigral neurons in Parkinson’s disease. Ann Neurol. 1999;46(6):920–4.PubMedCrossRefGoogle Scholar
  61. 61.
    Dexter DT, Carter CJ, Wells FR, Javoy-Agid F, Agid Y, Lees A, et al. Basal lipid peroxidation in substantia nigra is increased in Parkinson’s disease. J Neurochem. 1989;52(2):381–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Ramsey CP, Glass CA, Montgomery MB, et al. Expression of Nrf2 in neurodegenerative diseases. J Neuropathol Exp Neurol. 2007;66(1):75–85.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    van Muiswinkel FL, de Vos RA, Bol JG, et al. Expression of NAD(P)H:quinone oxidoreductase in the normal and parkinsonian substantia nigra. Neurobiol Aging. 2004;25(9):1253–62.PubMedCrossRefGoogle Scholar
  64. 64.
    Hwang O. Role of oxidative stress in Parkinson’s disease. Exp Neurobiol. 2013;22(1):11–7.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Schwarz DS, Blower MD. The endoplasmic reticulum: structure, function and response to cellular signaling. Cell Mol Life Sci. 2016;73(1):79–94.PubMedCrossRefGoogle Scholar
  66. 66.
    Hoozemans JJ, van Haastert ES, Eikelenboom P, de Vos RA, Rozemuller JM, Scheper W. Activation of the unfolded protein response in Parkinson’s disease. Biochem Biophys Res Commun. 2007;354(3):707–11.PubMedCrossRefGoogle Scholar
  67. 67.
    Bando Y, Katayama T, Taniguchi M, Ishibashi T, Matsuo N, Ogawa S, et al. RA410/Sly1 suppresses MPP+ and 6-hydroxydopamine-induced cell death in SH-SY5Y cells. Neurobiol Dis. 2005;18(1):143–51.PubMedCrossRefGoogle Scholar
  68. 68.
    Slodzinski H, Moran LB, Michael GJ, et al. Homocysteine-induced endoplasmic reticulum protein (herp) is up-regulated in parkinsonian substantia nigra and present in the core of Lewy bodies. Clin Neuropathol. 2009;28(5):333–43.PubMedGoogle Scholar
  69. 69.
    Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 1997;276(5321):2045–7.PubMedCrossRefGoogle Scholar
  70. 70.
    Siddiqui IJ, Pervaiz N, Abbasi AA. The Parkinson disease gene SNCA: evolutionary and structural insights with pathological implication. Sci Rep. 2016;6:24475.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Corti O, Lesage S, Brice A. What genetics tells us about the causes and mechanisms of Parkinson’s disease. Physiol Rev. 2011;91(4):1161–218.PubMedCrossRefGoogle Scholar
  72. 72.
    Sahin C, Kjaer L, Christensen MS, et al. Alpha-synuclein from animal species show low fibrillation propensity and low oligomer membrane disruption. Biochemistry. 2018.Google Scholar
  73. 73.
    Bendor JT, Logan TP, Edwards RH. The function of alpha-synuclein. Neuron. 2013;79(6):1044–66.PubMedCrossRefGoogle Scholar
  74. 74.
    Emamzadeh FN. Alpha-synuclein structure, functions, and interactions. J Res Med Sci. 2016;21:29.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Wakabayashi K, Tanji K, Mori F, Takahashi H. The Lewy body in Parkinson’s disease: molecules implicated in the formation and degradation of alpha-synuclein aggregates. Neuropathology. 2007;27(5):494–506.PubMedCrossRefGoogle Scholar
  76. 76.
    Fujiwara H, Hasegawa M, Dohmae N, et al. Alpha-synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol. 2002;4(2):160–4.PubMedCrossRefGoogle Scholar
  77. 77.
    Jang YY, Ye Z. Gene correction in patient-specific iPSCs for therapy development and disease modeling. Hum Genet. 2016;135(9):1041–58.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Bak RO, Gomez-Ospina N, Porteus MH. Gene editing on center stage. Trends Genet. 2018;34(8):600–11.PubMedCrossRefGoogle Scholar
  79. 79.
    Engel M, Do-Ha D, Munoz SS, Ooi L. Common pitfalls of stem cell differentiation: a guide to improving protocols for neurodegenerative disease models and research. Cell Mol Life Sci. 2016;73(19):3693–709.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Sances S, Bruijn LI, Chandran S, et al. Modeling ALS with motor neurons derived from human induced pluripotent stem cells. Nat Neurosci. 2016;19(4):542–53.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Studer L, Vera E, Cornacchia D. Programming and reprogramming cellular age in the era of induced pluripotency. Cell Stem Cell. 2015;16(6):591–600.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Sandor C, Robertson P, Lang C, et al. Transcriptomic profiling of purified patient-derived dopamine neurons identifies convergent perturbations and therapeutics for Parkinson’s disease. Hum Mol Genet. 2017;26(3):552–66.PubMedPubMedCentralGoogle Scholar
  83. 83.
    An N, Xu H, Gao WQ, Yang H. Direct conversion of somatic cells into induced neurons. Mol Neurobiol. 2018;55(1):642–51.PubMedCrossRefGoogle Scholar
  84. 84.
    Victor MB, Richner M, Olsen HE, et al. Striatal neurons directly converted from Huntington’s disease patient fibroblasts recapitulate age-associated disease phenotypes. Nat Neurosci. 2018;21(3):341–52.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Tang Y, Liu ML, Zang T, Zhang CL. Direct reprogramming rather than iPSC-based reprogramming maintains aging hallmarks in human motor neurons. Front Mol Neurosci. 2017;10:359.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Liu ML, Zang T, Zhang CL. Direct lineage reprogramming reveals disease-specific phenotypes of motor neurons from human ALS patients. Cell Rep. 2016;14(1):115–28.PubMedCrossRefGoogle Scholar
  87. 87.
    HD iPSC Consortium. Induced pluripotent stem cells from patients with Huntington’s disease show CAG repeat expansion-associated phenotypes. Cell Stem Cell. 2012;11(2):264–78.CrossRefGoogle Scholar
  88. 88.
    Camnasio S, Delli Carri A, Lombardo A, et al. The first reported generation of several induced pluripotent stem cell lines from homozygous and heterozygous Huntington’s disease patients demonstrates mutation related enhanced lysosomal activity. Neurobiol Dis. 2012;46(1):41–51.PubMedCrossRefGoogle Scholar
  89. 89.
    An MC, Zhang N, Scott G, et al. Genetic correction of Huntington’s disease phenotypes in induced pluripotent stem cells. Cell Stem Cell. 2012;11(2):253–63.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Caiazzo M, Dell'Anno MT, Dvoretskova E, et al. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature. 2011;476(7359):224–7.PubMedCrossRefGoogle Scholar
  91. 91.
    Pfisterer U, Kirkeby A, Torper O, et al. Direct conversion of human fibroblasts to dopaminergic neurons. Proc Natl Acad Sci U S A. 2011;108(25):10343–8.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Jiang H, Xu Z, Zhong P, et al. Cell cycle and p53 gate the direct conversion of human fibroblasts to dopaminergic neurons. Nat Commun. 2015;6:10100.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Mirakhori F, Zeynali B, Rassouli H, Salekdeh GH, Baharvand H. Direct conversion of human fibroblasts into dopaminergic neural progenitor-like cells using TAT-mediated protein transduction of recombinant factors. Biochem Biophys Res Commun. 2015;459(4):655–61.PubMedCrossRefGoogle Scholar
  94. 94.
    • Jo J, Xiao Y, Sun AX, et al. Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons. Cell Stem Cell. 2016;19(2):248–57 This paper describes an iPSC-derived midbrain organoid model that contains electrically active DA neurons and neuromelanin-producing neurons, offering another way to model PD using iPSCs. PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Qian X, Nguyen HN, Song MM, et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell. 2016;165(5):1238–54.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Tieng V, Stoppini L, Villy S, Fathi M, Dubois-Dauphin M, Krause KH. Engineering of midbrain organoids containing long-lived dopaminergic neurons. Stem Cells Dev. 2014;23(13):1535–47.PubMedCrossRefGoogle Scholar
  97. 97.
    Monzel AS, Smits LM, Hemmer K, et al. Derivation of human midbrain-specific organoids from neuroepithelial stem cells. Stem Cell Rep. 2017;8(5):1144–54.CrossRefGoogle Scholar
  98. 98.
    Hirsch EC, Hunot S. Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol. 2009;8(4):382–97.PubMedCrossRefGoogle Scholar
  99. 99.
    Gaig C, Vilas D, Infante J, et al. Nonmotor symptoms in LRRK2 G2019S associated Parkinson’s disease. PLoS One. 2014;9(10):e108982.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Pont-Sunyer C, Hotter A, Gaig C, Seppi K, Compta Y, Katzenschlager R, et al. The onset of nonmotor symptoms in Parkinson’s disease (the ONSET PD study). Mov Disord. 2015;30(2):229–37.PubMedCrossRefGoogle Scholar
  101. 101.
    van der Heeden JF, Marinus J, Martinez-Martin P, van Hilten JJ. Importance of nondopaminergic features in evaluating disease severity of Parkinson disease. Neurology. 2014;82(5):412–8.PubMedCrossRefGoogle Scholar
  102. 102.
    Mu L, Sobotka S, Chen J, Su H, Sanders I, Adler CH, et al. Alpha-synuclein pathology and axonal degeneration of the peripheral motor nerves innervating pharyngeal muscles in Parkinson disease. J Neuropathol Exp Neurol. 2013;72(2):119–29.3552335.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Wakabayashi K, Takahashi H. Neuropathology of autonomic nervous system in Parkinson’s disease. Eur Neurol. 1997;38(Suppl 2):2–7.PubMedCrossRefGoogle Scholar
  104. 104.
    Schondorf DC, Aureli M, McAllister FE, et al. iPSC-derived neurons from GBA1-associated Parkinson's disease patients show autophagic defects and impaired calcium homeostasis. Nat Commun. 2014;5:4028.PubMedCrossRefGoogle Scholar
  105. 105.
    Liu GH, Qu J, Suzuki K, et al. Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature. 2012;491(7425):603–7.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Fernandez-Santiago R, Carballo-Carbajal I, Castellano G, et al. Aberrant epigenome in iPSC-derived dopaminergic neurons from Parkinson's disease patients. EMBO Mol Med. 2015;7(12):1529–46.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Borgs L, Peyre E, Alix P, et al. Dopaminergic neurons differentiating from LRRK2 G2019S induced pluripotent stem cells show early neuritic branching defects. Sci Rep. 2016;6:33377 Region (SPW) and UCB pharma SA (Convention No. 1217666).PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    López de Maturana R, Lang V, Zubiarrain A, et al. Mutations in LRRK2 impair NF-κB pathway in iPSC-derived neurons. J Neuroinflamm. 2016;13(1):295.CrossRefGoogle Scholar
  109. 109.
    Ren Y, Jiang H, Hu Z, et al. Parkin Mutations Reduce the Complexity of Neuronal Processes in iPSC-Derived Human Neurons. Stem Cells. 2015;33(1):68–78.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Aboud AA, Tidball AM, Kumar KK, et al. PARK2 patient neuroprogenitors show increased mitochondrial sensitivity to copper. Neurobiol Dis. 2015;73:204–12.PubMedCrossRefGoogle Scholar
  111. 111.
    Konovalova EV, Lopacheva OM, Grivennikov IA, et al. Mutations in the Parkinson’s Disease-Associated PARK2 Gene Are Accompanied by Imbalance in Programmed Cell Death Systems. Acta Naturae. 2015;7(4):146–9.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Zhong P, Hu Z, Jiang H, Yan Z, Feng J. Dopamine Induces Oscillatory Activities in Human Midbrain Neurons with Parkin Mutations. Cell Reports. 2017;19(5):1033–44.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Ren Q, Ma M, Yang J, et al. Soluble epoxide hydrolase plays a key role in the pathogenesis of Parkinson’s disease. Proc Nat Acad Sci. 2018;115(25):E5815–E23.PubMedCrossRefGoogle Scholar
  114. 114.
    Seibler P, Graziotto J, Jeong H, Simunovic F, Klein C, Krainc D. Mitochondrial Parkin Recruitment Is Impaired in Neurons Derived from Mutant PINK1 Induced Pluripotent Stem Cells. J Neurosci. 2011;31(16):5970–6.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Devine MJ, Ryten M, Vodicka P, et al. Parkinson's disease induced pluripotent stem cells with triplication of the α-synuclein locus. Nat Commun. 2011;2:440.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Flierl A, Oliveira LMA, Falomir-Lockhart LJ, et al. Higher Vulnerability and Stress Sensitivity of Neuronal Precursor Cells Carrying an Alpha-Synuclein Gene Triplication. PLOS ONE. 2014;9(11):e112413.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Oliveira LMA, Falomir-Lockhart LJ, Botelho MG, et al. Elevated α-synuclein caused by SNCA gene triplication impairs neuronal differentiation and maturation in Parkinson's patient-derived induced pluripotent stem cells. Cell Death Dis. 2015;6:e1994.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Vasquez V, Mitra J, Hegde PM, et al. Chromatin-Bound Oxidized alpha-Synuclein Causes Strand Breaks in Neuronal Genomes in in vitro Models of Parkinson's Disease. J Alzheimers Dis. 2017;60(s1):S133–S50.PubMedCrossRefGoogle Scholar
  119. 119.
    George G, Singh S, Lokappa SB, Varkey J. Gene co-expression network analysis for identifying genetic markers in Parkinson’s disease - a three-way comparative approach. Genomics. 2018.Google Scholar
  120. 120.
    Marrone L, Bus C, Schöndorf D, et al. Generation of iPSCs carrying a common LRRK2 risk allele for in vitro modeling of idiopathic Parkinson’s disease. PloS One. 2018;13(3):e0192497.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • S. L. Sison
    • 1
  • S. C. Vermilyea
    • 2
    • 3
  • M. E. Emborg
    • 2
    • 3
    • 4
  • A. D. Ebert
    • 1
    • 5
  1. 1.Department of Cell Biology, Neurobiology and AnatomyMedical College of WisconsinMilwaukeeUSA
  2. 2.Neuroscience Training ProgramUniversity of Wisconsin-MadisonMadisonUSA
  3. 3.Preclinical Parkinson’s Research Program, Wisconsin National Primate Research CenterUniversity of Wisconsin-MadisonMadisonUSA
  4. 4.Department of Medical PhysicsUniversity of Wisconsin-MadisonMadisonUSA
  5. 5.Neuroscience Research CenterMedical College of WisconsinMilwaukeeUSA

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