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CRISPR System: A High-throughput Toolbox for Research and Treatment of Parkinson’s Disease

  • Fatemeh Safari
  • Gholamreza Hatam
  • Abbas Behzad Behbahani
  • Vahid Rezaei
  • Mazyar Barekati‑Mowahed
  • Peyman Petramfar
  • Farzaneh KhademiEmail author
Review Paper

Abstract

In recent years, the innovation of gene-editing tools such as the CRISPR/Cas9 system improves the translational gap of treatments mediated by gene therapy. The privileges of CRISPR/Cas9 such as working in living cells and organs candidate this technology for using in research and treatment of the central nervous system (CNS) disorders. Parkinson’s disease (PD) is a common, debilitating, neurodegenerative disorder which occurs due to loss of dopaminergic neurons and is associated with progressive motor dysfunction. Knowledge about the pathophysiological basis of PD has altered the classification system of PD, which manifests in familial and sporadic forms. The first genetic linkage studies in PD demonstrated the involvement of Synuclein alpha (SNCA) mutations and SNCA genomic duplications in the pathogenesis of PD familial forms. Subsequent studies have also insinuated mutations in leucine repeat kinase-2 (LRRK2), Parkin, PTEN-induced putative kinase 1 (PINK1), as well as DJ-1 causing familial forms of PD. This review will attempt to discuss the structure, function, and development in genome editing mediated by CRISP/Cas9 system. Further, it describes the genes involved in the pathogenesis of PD and the pertinent alterations to them. We will pursue this line by delineating the PD linkage studies in which CRISPR system was employed. Finally, we will discuss the pros and cons of CRISPR employment vis-à-vis the process of genome editing in PD patients’ iPSCs.

Keywords

Parkinson disease Gene editing CRISPR-associated protein 9 Induced pluripotent stem cells Neuroinflammation 

Notes

Funding

It is certified that no funding has been received for the preparation of this manuscript

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

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

Informed Consent

As no human participants are involved in this study no informed consent had been obtained.

References

  1. Abeliovich A et al (2000) Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25:239–252CrossRefGoogle Scholar
  2. Abizaid A et al (2006) Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J Clin Investig 116:3229–3239.  https://doi.org/10.1172/jci29867 CrossRefGoogle Scholar
  3. Abou-Sleiman PM, Healy DG, Quinn N, Lees AJ, Wood NW (2003) The role of pathogenic DJ-1 mutations in Parkinson’s disease. Ann Neurol 54(3):283–286.  https://doi.org/10.1002/ana.10675 CrossRefPubMedGoogle Scholar
  4. Ai SX et al (2014) Hypomethylation of SNCA in blood of patients with sporadic Parkinson’s disease. J Neurol Sci 337:123–128.  https://doi.org/10.1016/j.jns.2013.11.033 CrossRefPubMedGoogle Scholar
  5. Anand VS, Braithwaite SP (2009) LRRK2 in Parkinson’s disease: biochemical functions. FEBS J 276(22):6428–6435.  https://doi.org/10.1111/j.1742-4658.2009.07341.x CrossRefPubMedGoogle Scholar
  6. Andrews ZB et al (2009) Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism. J Neurosci 29(45):14057–14065.  https://doi.org/10.1523/jneurosci.3890-09.2009 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Annesi G et al (2005) DJ-1 mutations and parkinsonism-dementia-amyotrophic lateral sclerosis complex. Ann Neurol 58(5):803–807.  https://doi.org/10.1002/ana.20666 CrossRefPubMedGoogle Scholar
  8. Arkinson C, Walden H (2018) Parkin function in Parkinson’s disease. Science 360:267–268.  https://doi.org/10.1126/science.aar6606 CrossRefPubMedGoogle Scholar
  9. Arruda VR, Doshi BS, Samelson-Jones BJ (2017) Novel approaches to hemophilia therapy: successes and challenges. Blood 130:2251–2256.  https://doi.org/10.1182/blood-2017-08-742312 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Athauda D, Foltynie T (2016) Challenges in detecting disease modification in Parkinson’s disease clinical trials. Parkinsonism Relat Disord 32:1–11.  https://doi.org/10.1016/j.parkreldis.2016.07.019 CrossRefPubMedGoogle Scholar
  11. Basu S, Adams L, Guhathakurta S, Kim YS (2017) A novel tool for monitoring endogenous alpha-synuclein transcription by NanoLuciferase tag insertion at the 3′end using CRISPR-Cas9 genome editing technique. Sci Rep 7:45883.  https://doi.org/10.1038/srep45883 CrossRefPubMedCentralGoogle Scholar
  12. Blesa J, Przedborski S (2014) Parkinson’s disease: animal models and dopaminergic cell vulnerability. Front Neuroanat 8:155.  https://doi.org/10.3389/fnana.2014.00155 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Bonifati V et al (2002) Localization of autosomal recessive early-onset parkinsonism to chromosome 1p36 (PARK7) in an independent dataset. Ann Neurol 51(2):253–256CrossRefGoogle Scholar
  14. Bonifati V et al (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299(5604):256–259.  https://doi.org/10.1126/science.1077209 CrossRefPubMedGoogle Scholar
  15. Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318:121–134.  https://doi.org/10.1007/s00441-004-0956-9 CrossRefPubMedGoogle Scholar
  16. Byers B, Lee HL, Reijo Pera R (2012) Modeling Parkinson’s disease using induced pluripotent stem cells. Curr Neurol Neurosci Rep 12:237–242.  https://doi.org/10.1007/s11910-012-0270-y CrossRefPubMedPubMedCentralGoogle Scholar
  17. Chang D et al (2017) A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat Genet 49(10):1511–1516.  https://doi.org/10.1038/ng.3955 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Chen Y et al (2018) Engineering synucleinopathy-resistant human dopaminergic neurons by CRISPR-mediated deletion of the SNCA gene. Eur J Neurosci.  https://doi.org/10.1111/ejn.14286 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Cheng H et al (2002) Isolation and characterization of a human novel RAB (RAB39B) gene. Cytogenet Genome Res 97(1–2):72–75.  https://doi.org/10.1159/000064047 CrossRefPubMedGoogle Scholar
  20. Cheng MY, Bittman EL, Hattar S, Zhou QY (2005) Regulation of prokineticin 2 expression by light and the circadian clock. BMC Neurosci 6(1):17.  https://doi.org/10.1186/1471-2202-6-17 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Chesselet MF, Richter F (2011) Modelling of Parkinson’s disease in mice. Lancet Neurol 10:1108–1118.  https://doi.org/10.1016/s1474-4422(11)70227-7 CrossRefPubMedGoogle Scholar
  22. Chu Y, Kordower JH (2010) Lewy body pathology in fetal grafts. Ann N Y Acad Sci 1184:55–67.  https://doi.org/10.1111/j.1749-6632.2009.05229.x CrossRefPubMedGoogle Scholar
  23. Dawson TM, Golde TE, Lagier-Tourenne C (2018) Animal models of neurodegenerative diseases. Nat Neurosci 21:1370–1379.  https://doi.org/10.1038/s41593-018-0236-8 CrossRefPubMedPubMedCentralGoogle Scholar
  24. de Boni L, Tierling S, Roeber S, Walter J, Giese A, Kretzschmar HA (2011) Next-generation sequencing reveals regional differences of the alpha-synuclein methylation state independent of Lewy body disease. NeuroMol Med 13:310–320.  https://doi.org/10.1007/s12017-011-8163-9 CrossRefGoogle Scholar
  25. DeJesus R et al (2016) Functional CRISPR screening identifies the ufmylation pathway as a regulator of SQSTM1/p62. ELife 5:e17290.  https://doi.org/10.7554/elife.17290 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Dekel-Naftali M et al (2012) Screening of human pluripotent stem cells using CGH and FISH reveals low-grade mosaic aneuploidy and a recurrent amplification of chromosome 1q. Eur J Hum Genet 20(12):1248–1255.  https://doi.org/10.1038/ejhg.2012.128 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Devine MJ, Gwinn K, Singleton A, Hardy J (2011) Parkinson’s disease and alpha-synuclein expression. Mov Disord 26:2160–2168.  https://doi.org/10.1002/mds.23948 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Dolezalova D et al (2014) Pig models of neurodegenerative disorders: utilization in cell replacement-based preclinical safety and efficacy studies. J Comp Neurol 522:2784–2801.  https://doi.org/10.1002/cne.23575 CrossRefPubMedGoogle Scholar
  29. Emamalizadeh B et al (2014) RIT2, a susceptibility gene for Parkinson’s disease in Iranian population. Neurobiol Aging 35(12):e27–e28.  https://doi.org/10.1016/j.neurobiolaging.2014.07.013 CrossRefPubMedGoogle Scholar
  30. Farrer M et al (2004) Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. Ann Neurol 55:174–179.  https://doi.org/10.1002/ana.10846 CrossRefPubMedGoogle Scholar
  31. Ferreira M, Massano J (2017) An updated review of Parkinson’s disease genetics and clinicopathological correlations. Acta Neurol Scand 135:273–284.  https://doi.org/10.1111/ane.12616 CrossRefPubMedGoogle Scholar
  32. Flierl A et al (2014) Higher vulnerability and stress sensitivity of neuronal precursor cells carrying an alpha-synuclein gene triplication. PLoS ONE 9:e112413.  https://doi.org/10.1371/journal.pone.0112413 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Floyd BJ et al (2016) Mitochondrial protein interaction mapping identifies regulators of respiratory chain function. Mol Cell 63:621–632.  https://doi.org/10.1016/j.molcel.2016.06.033 CrossRefPubMedPubMedCentralGoogle Scholar
  34. Fu Y, Foden JA, Khayter C, Maeder ML, Reyon D, Joung JK, Sander JD (2013) High-frequency off-target mutagenesis induced by CRISPR-Cas nucleases in human cells. Nat Biotechnol 31:822–826.  https://doi.org/10.1038/nbt.2623 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Fujiwara H et al (2002) α-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4(2):160–164.  https://doi.org/10.1038/ncb748 CrossRefPubMedGoogle Scholar
  36. Gaj T, Gersbach CA, Barbas CF III (2013) ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol 31(7):397–405.  https://doi.org/10.1016/j.tibtech.2013.04.004 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Gao Y, Wilson GR, Bozaoglu K, Elefanty AG, Stanley EG, Dottori M, Lockhart PJ (2018) Generation of RAB39B knockout isogenic human embryonic stem cell lines to model RAB39B-mediated Parkinson’s disease. Stem Cell Res 28:161–164.  https://doi.org/10.1016/j.scr.2018.02.015 CrossRefPubMedGoogle Scholar
  38. Ghosh A et al (2016) Mitoapocynin treatment protects against neuroinflammation and dopaminergic neurodegeneration in a preclinical animal model of parkinson’s disease. J Neuroimmune Pharmacol 11:259–278.  https://doi.org/10.1007/s11481-016-9650-4 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Gorbatyuk OS et al (2010) In vivo RNAi-mediated alpha-synuclein silencing induces nigrostriatal degeneration. Mol Ther 18:1450–1457.  https://doi.org/10.1038/mt.2010.115 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Gordon R, Anantharam V, Kanthasamy AG, Kanthasamy A (2012) Proteolytic activation of proapoptotic kinase protein kinase Cdelta by tumor necrosis factor alpha death receptor signaling in dopaminergic neurons during neuroinflammation. J Neuroinflammation 9:82.  https://doi.org/10.1186/1742-2094-9-82 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Gordon R et al (2016a) Prokineticin-2 upregulation during neuronal injury mediates a compensatory protective response against dopaminergic neuronal degeneration. Nat Commun 7:12932.  https://doi.org/10.1038/ncomms12932 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Gordon R et al (2016b) Protein kinase Cdelta upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson’s disease. Neurobiol Dis 93:96–114.  https://doi.org/10.1016/j.nbd.2016.04.008 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Gore A et al (2011) Somatic coding mutations in human induced pluripotent stem cells. Nature 471:63–67.  https://doi.org/10.1038/nature09805 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Grundemann J, Schlaudraff F, Haeckel O, Liss B (2008) Elevated alpha-synuclein mRNA levels in individual UV-laser-microdissected dopaminergic substantia nigra neurons in idiopathic Parkinson’s disease. Nucleic Acids Res 36:e38.  https://doi.org/10.1093/nar/gkn084 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Guhathakurta S, Bok E, Evangelista BA, Kim YS (2017) Deregulation of alpha-synuclein in Parkinson’s disease: insight from epigenetic structure and transcriptional regulation of SNCA. Prog Neurobiol 154:21–36.  https://doi.org/10.1016/j.pneurobio.2017.04.004 CrossRefPubMedPubMedCentralGoogle Scholar
  46. Hanrott K, Murray TK, Orfali Z, Ward M, Finlay C, O’Neill MJ, Wonnacott S (2008) Differential activation of PKC delta in the substantia nigra of rats following striatal or nigral 6-hydroxydopamine lesions. Eur J Neurosci 27(5):1086–1096.  https://doi.org/10.1111/j.1460-9568.2008.06097.x CrossRefPubMedGoogle Scholar
  47. Hasegawa K, Stoessl AJ, Yokoyama T, Kowa H, Wszolek ZK, Yagishita S (2009) Familial parkinsonism: study of original Sagamihara PARK8 (I2020T) kindred with variable clinicopathologic outcomes. Parkinsonism Relat Disord 15(4):300–306.  https://doi.org/10.1016/j.parkreldis.2008.07.010 CrossRefPubMedGoogle Scholar
  48. Healy DG et al (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol 7(7):583–590.  https://doi.org/10.1016/s1474-4422(08)70117-0 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Higashi S et al (2015) p13 overexpression in pancreatic beta-cells ameliorates type 2 diabetes in high-fat-fed mice. Biochem Biophys Res Commun 461(4):612–617.  https://doi.org/10.1016/j.bbrc.2015.04.074 CrossRefPubMedGoogle Scholar
  50. Hussein SM et al (2011) Copy number variation and selection during reprogramming to pluripotency. Nature 471:58–62.  https://doi.org/10.1038/nature09871 CrossRefPubMedGoogle Scholar
  51. Inoue N et al (2018) Knockdown of the mitochondria-localized protein p13 protects against experimental parkinsonism. EMBO Rep.  https://doi.org/10.15252/embr.201744860 CrossRefPubMedPubMedCentralGoogle Scholar
  52. Jamshidi J et al (2014) HLA-DRA is associated with Parkinson’s disease in Iranian population. Int J Immunogenet 41:508–511.  https://doi.org/10.1111/iji.12151 CrossRefPubMedGoogle Scholar
  53. Jian F et al (2018) Sam50 Regulates PINK1-Parkin-mediated mitophagy by controlling PINK1 stability and mitochondrial morphology. Cell Rep 23(10):2989–3005.  https://doi.org/10.1016/j.celrep.2018.05.015 CrossRefPubMedGoogle Scholar
  54. Jowaed A, Schmitt I, Kaut O, Wullner U (2010) Methylation regulates alpha-synuclein expression and is decreased in Parkinson’s disease patients’ brains. J Neurosci 30:6355–6359.  https://doi.org/10.1523/jneurosci.6119-09.2010 CrossRefPubMedPubMedCentralGoogle Scholar
  55. Kantor B et al (2018) Downregulation of SNCA expression by targeted editing of DNA methylation: a potential strategy for precision therapy in PD. Mol Ther 26:2638–2649.  https://doi.org/10.1016/j.ymthe.2018.08.019 CrossRefPubMedPubMedCentralGoogle Scholar
  56. Khodr CE et al (2011) An alpha-synuclein AAV gene silencing vector ameliorates a behavioral deficit in a rat model of Parkinson’s disease, but displays toxicity in dopamine neurons. Brain Res 1395:94–107.  https://doi.org/10.1016/j.brainres.2011.04.036 CrossRefPubMedPubMedCentralGoogle Scholar
  57. Kim HJ, Jeon BS, Yoon MY, Park SS, Lee KW (2012) Increased expression of alpha-synuclein by SNCA duplication is associated with resistance to toxic stimuli. J Mol Neurosci 47:249–255.  https://doi.org/10.1007/s12031-012-9732-6 CrossRefPubMedGoogle Scholar
  58. Kitada T et al (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608.  https://doi.org/10.1038/33416 CrossRefPubMedGoogle Scholar
  59. Knott GJ, Doudna JA (2018) CRISPR-Cas guides the future of genetic engineering. Science 361(6405):866–869.  https://doi.org/10.1126/science.aat5011 CrossRefPubMedPubMedCentralGoogle Scholar
  60. Lazarou M et al (2015) The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524(7565):309–314.  https://doi.org/10.1038/nature14893 CrossRefPubMedPubMedCentralGoogle Scholar
  61. Lesage S et al (2015) Loss-of-function mutations in RAB39B are associated with typical early-onset Parkinson disease. Neurol Genet 1(1):e9.  https://doi.org/10.1212/nxg.0000000000000009 CrossRefPubMedPubMedCentralGoogle Scholar
  62. Li JY 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.  https://doi.org/10.1038/nm1746 CrossRefPubMedGoogle Scholar
  63. Li W et al (2016) Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Proc Natl Acad Sci USA 113(23):6544–6549.  https://doi.org/10.1073/pnas.1605245113 CrossRefPubMedGoogle Scholar
  64. Liao HK et al (2017) In vivo target gene activation via CRISPR/Cas9-mediated trans-epigenetic modulation. Cell 171(7):1495–1507.  https://doi.org/10.1016/j.cell.2017.10.025 CrossRefPubMedPubMedCentralGoogle Scholar
  65. Liddelow SA et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–487.  https://doi.org/10.1038/nature21029 CrossRefPubMedPubMedCentralGoogle Scholar
  66. Lincoln SJ et al (2003) Parkin variants in North American Parkinson’s disease: cases and controls. Mov Disord 18:1306–1311.  https://doi.org/10.1002/mds.10601 CrossRefPubMedGoogle Scholar
  67. Lindvall O et al (1990) Grafts of fetal dopamine neurons survive and improve motor function in Parkinson’s disease. Science 247(4942):574–577CrossRefGoogle Scholar
  68. Liu XS et al (2018) Rescue of fragile X syndrome neurons by DNA methylation editing of the FMR1 gene. Cell 172(5):979–992.  https://doi.org/10.1016/j.cell.2018.01.012 CrossRefPubMedPubMedCentralGoogle Scholar
  69. Lohmann E et al (2003) How much phenotypic variation can be attributed to parkin genotype? Ann Neurol 54:176–185.  https://doi.org/10.1002/ana.10613 CrossRefPubMedGoogle Scholar
  70. Lubbe S, Morris HR (2014) Recent advances in Parkinson’s disease genetics. J Neurol 261:259–266.  https://doi.org/10.1007/s00415-013-7003-2 CrossRefPubMedGoogle Scholar
  71. Luk KC, Kehm V, Carroll J, Zhang B, O’Brien P, Trojanowski JQ, Lee VM (2012) Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338(6109):949–953.  https://doi.org/10.1126/science.1227157 CrossRefPubMedPubMedCentralGoogle Scholar
  72. Luo J et al (2019) Utilization of the CRISPR-Cas9 gene editing system to dissect neuroinflammatory and neuropharmacological mechanisms in parkinson’s disease. J Neuroimmune Pharmacol.  https://doi.org/10.1007/s11481-019-09844-3 CrossRefPubMedGoogle Scholar
  73. Marin I (2008) Ancient origin of the Parkinson disease gene LRRK2. J Mol Evol 67(1):41–50.  https://doi.org/10.1007/s00239-008-9122-4 CrossRefPubMedGoogle Scholar
  74. Matsumoto L, Takuma H, Tamaoka A, Kurisaki H, Date H, Tsuji S, Iwata A (2010) CpG demethylation enhances alpha-synuclein expression and affects the pathogenesis of Parkinson’s disease. PLoS ONE 5:e15522.  https://doi.org/10.1371/journal.pone.0015522 CrossRefPubMedPubMedCentralGoogle Scholar
  75. McCormack AL, Mak SK, Henderson JM, Bumcrot D, Farrer MJ, Di Monte DA (2010) Alpha-synuclein suppression by targeted small interfering RNA in the primate substantia nigra. PLoS ONE 5:e12122.  https://doi.org/10.1371/journal.pone.0012122 CrossRefPubMedPubMedCentralGoogle Scholar
  76. McCoy MK, Kaganovich A, Rudenko IN, Ding J, Cookson MR (2014) Hexokinase activity is required for recruitment of parkin to depolarized mitochondria. Hum Mol Genet 23:145–156.  https://doi.org/10.1093/hmg/ddt407 CrossRefPubMedGoogle Scholar
  77. Meier ID et al (2010) Short DNA sequences inserted for gene targeting can accidentally interfere with off-target gene expression. FASEB J 24:1714–1724.  https://doi.org/10.1096/fj.09-140749 CrossRefPubMedGoogle Scholar
  78. Mori H et al (1998) Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q. Neurology 51(3):890–892CrossRefGoogle Scholar
  79. Murlidharan G et al (2016) CNS-restricted transduction and CRISPR/Cas9-mediated gene deletion with an engineered AAV vector. Mol Ther 5:e338.  https://doi.org/10.1038/mtna.2016.49 CrossRefGoogle Scholar
  80. Nasrolahi A et al (2019) Immune system and new avenues in Parkinson’s disease research and treatment. Rev Neurosci.  https://doi.org/10.1515/revneuro-2018-0105 CrossRefPubMedGoogle Scholar
  81. Neal M et al (2018) Prokineticin-2 promotes chemotaxis and alternative A2 reactivity of astrocytes. Glia 66(10):2137–2157.  https://doi.org/10.1002/glia.23467 CrossRefPubMedPubMedCentralGoogle Scholar
  82. Neumann J et al (2009) Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease. Brain 132:1783–1794.  https://doi.org/10.1093/brain/awp044 CrossRefPubMedPubMedCentralGoogle Scholar
  83. Nguyen HN et al (2011) LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell stem cell 8(3):267–280.  https://doi.org/10.1016/j.stem.2011.01.013 CrossRefPubMedPubMedCentralGoogle Scholar
  84. Nuytemans K, Theuns J, Cruts M, Van Broeckhoven C (2010) Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update. Hum Mutat 31(7):763–780.  https://doi.org/10.1002/humu.21277 CrossRefPubMedPubMedCentralGoogle Scholar
  85. Osterstock G et al (2010) Ghrelin stimulation of growth hormone-releasing hormone neurons is direct in the arcuate nucleus. PLoS ONE 5:e9159.  https://doi.org/10.1371/journal.pone.0009159 CrossRefPubMedPubMedCentralGoogle Scholar
  86. Panicker N, Dawson VL, Dawson TM (2017) Activation mechanisms of the E3 ubiquitin ligase parkin. Biochem J 474(18):3075–3086.  https://doi.org/10.1042/bcj20170476 CrossRefPubMedGoogle Scholar
  87. Piccini P et al (2005) Factors affecting the clinical outcome after neural transplantation in Parkinson’s disease. Brain 128:2977–2986.  https://doi.org/10.1093/brain/awh649 CrossRefPubMedGoogle Scholar
  88. Piper DA, Sastre D, Schule B (2018) Advancing stem cell models of alpha-synuclein gene regulation in neurodegenerative disease. Front Neurosci 12:199.  https://doi.org/10.3389/fnins.2018.00199 CrossRefPubMedPubMedCentralGoogle Scholar
  89. Pitteloud N et al (2007) Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci USA 104(44):17447–17452.  https://doi.org/10.1073/pnas.0707173104 CrossRefPubMedGoogle Scholar
  90. Politis M et al (2010) Serotonergic neurons mediate dyskinesia side effects in Parkinson’s patients with neural transplants. Sci Transl Med 2(38):38ra46.  https://doi.org/10.1126/scitranslmed.3000976 CrossRefPubMedGoogle Scholar
  91. Polymeropoulos MH et al (1996) Mapping of a gene for Parkinson’s disease to chromosome 4q21-q23. Science 274(5290):1197–1199CrossRefGoogle Scholar
  92. Potting C et al (2018) Genome-wide CRISPR screen for PARKIN regulators reveals transcriptional repression as a determinant of mitophagy. Proc Natl Acad Sci USA 115:E180–E189.  https://doi.org/10.1073/pnas.1711023115 CrossRefPubMedGoogle Scholar
  93. Pramstaller PP et al (2005) Lewy body Parkinson’s disease in a large pedigree with 77 Parkin mutation carriers. Ann Neurol 58(3):411–422.  https://doi.org/10.1002/ana.20587 CrossRefPubMedGoogle Scholar
  94. Qing X, Walter J, Jarazo J, Arias-Fuenzalida J, Hillje AL, Schwamborn JC (2017) CRISPR/Cas9 and piggyBac-mediated footprint-free LRRK2-G2019S knock-in reveals neuronal complexity phenotypes and alpha-Synuclein modulation in dopaminergic neurons. Stem Cell Res 24:44–50.  https://doi.org/10.1016/j.scr.2017.08.013 CrossRefPubMedGoogle Scholar
  95. Ran FA et al (2013) Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell 154(6):1380–1389.  https://doi.org/10.1016/j.cell.2013.08.021 CrossRefPubMedPubMedCentralGoogle Scholar
  96. Reinhardt P et al (2013) Derivation and expansion using only small molecules of human neural progenitors for neurodegenerative disease modeling. PLoS ONE 8:e59252.  https://doi.org/10.1371/journal.pone.0059252 CrossRefPubMedPubMedCentralGoogle Scholar
  97. Rose CM et al (2016) Highly multiplexed quantitative mass spectrometry analysis of ubiquitylomes. Cell Syst 3(395–403):e394.  https://doi.org/10.1016/j.cels.2016.08.009 CrossRefGoogle Scholar
  98. Safari F, Tamaddon AM, Zarghami N, Abolmali S, Akbarzadeh A (2016) Polyelectrolyte complexes of hTERT siRNA and polyethyleneimine: effect of degree of PEG grafting on biological and cellular activity. Artif Cells Nanomed Biotechnol 44(6):1561–1568.  https://doi.org/10.3109/21691401.2015.1064936 CrossRefPubMedGoogle Scholar
  99. Safari F, Rahmani Barouji S, Tamaddon AM (2017) Strategies for improving siRNA-induced gene silencing efficiency. Adv Pharm Bull 7:603–609.  https://doi.org/10.15171/apb.2017.072 CrossRefPubMedPubMedCentralGoogle Scholar
  100. Safari F, Zare K, Negahdaripour M, Barekati-Mowahed M, Ghasemi Y (2019) CRISPR Cpf1 proteins: structure, function and implications for genome editing. Cell Biosci 9:36.  https://doi.org/10.1186/s13578-019-0298-7 CrossRefGoogle Scholar
  101. Samaranch L et al (2010) PINK1-linked parkinsonism is associated with Lewy body pathology. Brain 133(4):1128–1142.  https://doi.org/10.1093/brain/awq051 CrossRefPubMedGoogle Scholar
  102. Sanchez-Danes A 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.  https://doi.org/10.1002/emmm.201200215 CrossRefPubMedPubMedCentralGoogle Scholar
  103. Sanders LH 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.  https://doi.org/10.1016/j.nbd.2013.10.013 CrossRefPubMedGoogle Scholar
  104. Sarkar S et al (2017) Mitochondrial impairment in microglia amplifies NLRP3 inflammasome proinflammatory signaling in cell culture and animal models of Parkinson’s disease. NPJ 3(1):30.  https://doi.org/10.1038/s41531-017-0032-2 CrossRefGoogle Scholar
  105. Schrag A (2018) Testing the MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 33:1518–1520.  https://doi.org/10.1002/mds.27543 CrossRefPubMedGoogle Scholar
  106. Scott L, Dawson VL, Dawson TM (2017) Trumping neurodegeneration: targeting common pathways regulated by autosomal recessive Parkinson’s disease genes. Exp Neurol 298:191–201.  https://doi.org/10.1016/j.expneurol.2017.04.008 CrossRefPubMedPubMedCentralGoogle Scholar
  107. Shi L et al (2013) Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels. Nat Commun 4:1435.  https://doi.org/10.1038/ncomms2439 CrossRefPubMedGoogle Scholar
  108. Solberg N, Krauss S (2013) Luciferase assay to study the activity of a cloned promoter DNA fragment. Methods Mol Biol 977:65–78.  https://doi.org/10.1007/978-1-62703-284-1_6 CrossRefPubMedGoogle Scholar
  109. Soldner F et al (2016) Parkinson-associated risk variant in distal enhancer of alpha-synuclein modulates target gene expression. Nature 533:95–99.  https://doi.org/10.1038/nature17939 CrossRefPubMedPubMedCentralGoogle Scholar
  110. Song C et al (2019) Mechanistic interplay between autophagy and apoptotic signaling in endosulfan-induced dopaminergic neurotoxicity: relevance to the adverse outcome pathway in pesticide neurotoxicity. Toxicol Sci.  https://doi.org/10.1093/toxsci/kfz049 CrossRefPubMedGoogle Scholar
  111. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840.  https://doi.org/10.1038/42166 CrossRefPubMedGoogle Scholar
  112. Suda Y et al (2018) Down-regulation of ghrelin receptors on dopaminergic neurons in the substantia nigra contributes to Parkinson’s disease-like motor dysfunction. Mol Brain 11:6.  https://doi.org/10.1186/s13041-018-0349-8 CrossRefPubMedPubMedCentralGoogle Scholar
  113. Taghavi S et al (2018) A clinical and molecular genetic study of 50 families with autosomal recessive parkinsonism revealed known and novel gene mutations. Mol Neurobiol 55(4):3477–3489.  https://doi.org/10.1007/s12035-017-0535-1 CrossRefPubMedGoogle Scholar
  114. Tagliafierro L, Chiba-Falek O (2016) Up-regulation of SNCA gene expression: implications to synucleinopathies. Neurogenetics 17:145–157.  https://doi.org/10.1007/s10048-016-0478-0 CrossRefPubMedPubMedCentralGoogle Scholar
  115. Taipa R, Pereira C, Reis I, Alonso I, Bastos-Lima A, Melo-Pires M, Magalhaes M (2016) DJ-1 linked parkinsonism (PARK7) is associated with Lewy body pathology. Brain 139(6):1680–1687.  https://doi.org/10.1093/brain/aww080 CrossRefPubMedGoogle Scholar
  116. Takahashi M et al (2015) Normalization of overexpressed alpha-synuclein causing parkinson’s disease by a moderate gene silencing with rna interference. Mol Ther 4:e241.  https://doi.org/10.1038/mtna.2015.14 CrossRefGoogle Scholar
  117. Valente EM et al (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304(5674):1158–1160.  https://doi.org/10.1126/science.1096284 CrossRefPubMedGoogle Scholar
  118. Vasil’eva EA, Melino D, Barlev NA (2015) CRISPR/Cas system for genome editing in pluripotent stem cells. Tsitologiia 57(1):19–30PubMedGoogle Scholar
  119. Vetchinova AS et al (2018) Cytogenetic analysis of the results of genome editing on the cell model of parkinson’s disease. Bull Exp Biol Med.  https://doi.org/10.1007/s10517-018-4174-y CrossRefPubMedGoogle Scholar
  120. Volpicelli-Daley LA et al (2011) Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72:57–71.  https://doi.org/10.1016/j.neuron.2011.08.033 CrossRefPubMedPubMedCentralGoogle Scholar
  121. Wang Y, Wang X, Li R, Yang ZF, Wang YZ, Gong XL, Wang XM (2013) A DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine, exacerbates neurotoxicity and upregulates Parkinson’s disease-related genes in dopaminergic neurons. CNS Neurosci Ther 19(3):183–190.  https://doi.org/10.1111/cns.12059 CrossRefPubMedPubMedCentralGoogle Scholar
  122. Wang X et al (2016) One-step generation of triple gene-targeted pigs using CRISPR/Cas9 system. Sci Rep 6:20620.  https://doi.org/10.1038/srep20620 CrossRefPubMedPubMedCentralGoogle Scholar
  123. Wilson GR et al (2014) Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with alpha-synuclein pathology. Am J Hum Genet 95(6):729–735.  https://doi.org/10.1016/j.ajhg.2014.10.015 CrossRefPubMedPubMedCentralGoogle Scholar
  124. Yao J, Huang J, Zhao J (2016) Genome editing revolutionize the creation of genetically modified pigs for modeling human diseases. Hum Genet 135:1093–1105.  https://doi.org/10.1007/s00439-016-1710-6 CrossRefPubMedGoogle Scholar
  125. Ye L et al (2014) Seamless modification of wild-type induced pluripotent stem cells to the natural CCR5Delta32 mutation confers resistance to HIV infection. Proc Natl Acad Sci USA 111(26):9591–9596.  https://doi.org/10.1073/pnas.1407473111 CrossRefPubMedGoogle Scholar
  126. Zhang D, Kanthasamy A, Yang Y, Anantharam V, Kanthasamy A (2007) Protein kinase C delta negatively regulates tyrosine hydroxylase activity and dopamine synthesis by enhancing protein phosphatase-2A activity in dopaminergic neurons. J Neurosci 27(20):5349–5362.  https://doi.org/10.1523/jneurosci.4107-06.2007 CrossRefPubMedPubMedCentralGoogle Scholar
  127. Zhu M (1861) S HP, Han S (2017) DJ-1, a Parkinson’s disease related protein, aggregates under denaturing conditions and co-aggregates with alpha-synuclein through hydrophobic interaction. Biochim et Biophys Acta 7:1759–1769.  https://doi.org/10.1016/j.bbagen.2017.03.013 CrossRefGoogle Scholar
  128. Zhu XX, Zhong YZ, Ge YW, Lu KH, Lu SS (2018) CRISPR/Cas9-mediated generation of guangxi bama minipigs harboring three mutations in alpha-synuclein causing parkinson’s disease. Sci Rep 8(1):12420.  https://doi.org/10.1038/s41598-018-30436-3 CrossRefPubMedPubMedCentralGoogle Scholar
  129. Zimprich A et al (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44(4):601–607.  https://doi.org/10.1016/j.neuron.2004.11.005 CrossRefPubMedGoogle Scholar
  130. Zou J, Mali P, Huang X, Dowey SN, Cheng L (2011) Site-specific gene correction of a point mutation in human iPS cells derived from an adult patient with sickle cell disease. Blood 118:4599–4608.  https://doi.org/10.1182/blood-2011-02-335554 CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Medical Biotechnology, School of Advanced Medical Sciences and TechnologiesShiraz University of Medical SciencesShirazIran
  2. 2.Basic Sciences in Infectious Diseases Research Center, School of Advanced Medical Sciences and TechnologiesShiraz University of Medical SciencesShirazIran
  3. 3.Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical SciencesShiraz University of Medical SciencesShirazIran
  4. 4.Department of Medical Nanotechnology, School of Advanced Medical Sciences and TechnologiesShiraz University of Medical SciencesShirazIran
  5. 5.Department of Physiology & Biophysics, School of MedicineCase Western Reserve UniversityOhioUSA
  6. 6.Department of Neurology, Clinical Neurology Research CenterShiraz University of Medical SciencesShirazIran
  7. 7.Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and TechnologiesShiraz University of Medical SciencesShirazIran

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