Skip to content
2000
Volume 24, Issue 5
  • ISSN: 1871-5273
  • E-ISSN: 1996-3181

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder that results from the progressive loss of neurons in the brain followed by symptoms such as slowness and rigidity in movement, sleep disorders, dementia and many more. The different mechanisms due to which the neuronal degeneration occurs have been discussed, such as mutation in PD related genes, formation of Lewy bodies, oxidation of dopamine. This review discusses current surgical treatment and gene therapies with novel developments proposed for PD. Gene therapy based on novel approaches will possess more potential advantages over the conventional methods. Currently, gene therapy for such disorders is still under the process of clinical trials and approval. The pathogenesis comes from the breakdown of dopaminergic neurons within substantia nigra (SN) by the action of tyrosinase enzyme and subsequent accumulation of α-synuclein within the neurons. These dopaminergic neurons are the main source of dopamine, the decline of which is responsible for the symptoms. So, gene therapy can possibly provide more stable supplementation and regulate the expression of tyrosinase enzyme, providing better symptomatic relief and lesser side effects. Dopamine replacement therapy is a well-studied gene therapy method for PD. Another approach involves introducing functional genes for enzymes such as tyrosine hydroxylase, cyclohydrolases, and decarboxylases with the help of engineered vectors such as AAV and LV. Further, the potential application of nanoparticles in gene therapy as an efficient gene delivery and imaging system has been discussed. Among these, lipid-based nanoparticles such as PILs offer important benefits in terms of enhanced bioavailability, permeability to the cells, and solubility. So, this review paper summarizes some of the advanced gene therapy approaches for PD and the current status of clinical research in the development of gene therapy using nanoparticles.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cnsnddt/10.2174/0118715273336139241211071748
2025-01-13
2025-09-17

  • From This Site

    /content/journals/cnsnddt/10.2174/0118715273336139241211071748
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. JellingerK.A. Basic mechanisms of neurodegeneration: A critical update.J. Cell. Mol. Med.201014345748710.1111/j.1582‑4934.2010.01010.x 20070435
     [Google Scholar]
  2. LeverenzJ.B. QuinnJ.F. ZabetianC. ZhangJ. MontineK.S. MontineT.J. Cognitive impairment and dementia in patients with Parkinson disease.Curr. Top. Med. Chem.2009910903912 19754405
     [Google Scholar]
  3. NuytemansK. TheunsJ. CrutsM. Van BroeckhovenC. Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: A mutation update.Hum. Mutat.201031776378010.1002/humu.21277 20506312
     [Google Scholar]
  4. AdejareA. Drug Discovery Approaches for the Treatment of Neurodegenerative Disorders.Academic Press201610.1016/C2014‑0‑03514‑9
     [Google Scholar]
  5. FunayamaM. NishiokaK. LiY. HattoriN. Molecular genetics of Parkinson’s disease: Contributions and global trends.J. Hum. Genet.202368312513010.1038/s10038‑022‑01058‑5 35821405
     [Google Scholar]
  6. Bandres-CigaS. Diez-FairenM. KimJ.J. SingletonA.B. Genetics of Parkinson’s disease: An introspection of its journey towards precision medicine.Neurobiol. Dis.202013710478210.1016/j.nbd.2020.104782 31991247
     [Google Scholar]
  7. LeW. PanT. HuangM. Decreased NURR1 gene expression in patients with Parkinson’s disease.J. Neurol. Sci.20082731-2293310.1016/j.jns.2008.06.007 18684475
     [Google Scholar]
  8. GoldsteinD.S. SullivanP. HolmesC. KopinI.J. BasileM.J. MashD.C. Catechols in post-mortem brain of patients with Parkinson disease.Eur. J. Neurol.201118570371010.1111/j.1468‑1331.2010.03246.x 21073636
     [Google Scholar]
  9. VanItallieT.B. Parkinson disease: Primacy of age as a risk factor for mitochondrial dysfunction.Metabolism200857Suppl. 2S50S5510.1016/j.metabol.2008.07.015 18803967
     [Google Scholar]
  10. RamirezA. HeimbachA. GründemannJ. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase.Nat. Genet.200638101184119110.1038/ng1884 16964263
     [Google Scholar]
  11. JoselinA.P. HewittS.J. CallaghanS.M. ROS-dependent regulation of Parkin and DJ-1 localization during oxidative stress in neurons.Hum. Mol. Genet.201221224888490310.1093/hmg/dds325 22872702
     [Google Scholar]
  12. BekrisL.M. MataI.F. ZabetianC.P. The genetics of Parkinson disease.J. Geriatr. Psychiatry Neurol.201023422824210.1177/0891988710383572 20938043
     [Google Scholar]
  13. StraussK.M. MartinsL.M. Plun-FavreauH. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson’s disease.Hum. Mol. Genet.200514152099211110.1093/hmg/ddi215 15961413
     [Google Scholar]
  14. FangY.Q. MaoF. ZhuM.J. LiX.H. Compound heterozygous mutations in PARK2 causing early-onset Parkinson disease.Medicine (Baltimore)2019985e1422810.1097/MD.0000000000014228 30702579
     [Google Scholar]
  15. BakulaD. Scheibye-KnudsenM. MitophAging: Mitophagy in aging and disease.Front. Cell Dev. Biol.2020823910.3389/fcell.2020.00239 32373609
     [Google Scholar]
  16. JohansenK.K. TorpS.H. FarrerM.J. GustavssonE.K. AaslyJ.O. A case of Parkinson’s disease with no lewy body pathology due to a homozygous exon deletion in Parkin.Case Rep. Neurol. Med.201820181410.1155/2018/6838965 30050705
     [Google Scholar]
  17. MizushimaN. LevineB. CuervoA.M. KlionskyD.J. Autophagy fights disease through cellular self-digestion.Nature200845171821069107510.1038/nature06639 18305538
     [Google Scholar]
  18. KomatsuM. WaguriS. ChibaT. Loss of autophagy in the central nervous system causes neurodegeneration in mice.Nature2006441709588088410.1038/nature04723 16625205
     [Google Scholar]
  19. Gan-OrZ. DionP.A. RouleauG.A. Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease.Autophagy20151191443145710.1080/15548627.2015.1067364 26207393
     [Google Scholar]
  20. HasegawaT. Tyrosinase-expressing neuronal cell line as in vitro model of Parkinson’s disease.Int. J. Mol. Sci.20101131082108910.3390/ijms11031082 20480001
     [Google Scholar]
  21. LillC.M. Genetics of Parkinson’s disease.Mol. Cell. Probes201630638639610.1016/j.mcp.2016.11.001 27818248
     [Google Scholar]
  22. KleinC. WestenbergerA. Genetics of Parkinson’s disease.Cold Spring Harb. Perspect. Med.201221a008888a810.1101/cshperspect.a008888 22315721
     [Google Scholar]
  23. PolymeropoulosM.H. HigginsJ.J. GolbeL.I. Mapping of a gene for Parkinson’s disease to chromosome 4q21-q23.Science199627452901197119910.1126/science.274.5290.1197 8895469
     [Google Scholar]
  24. KumarK. Djarmati-WestenbergerA. GrünewaldA. Genetics of Parkinson’s disease.Semin. Neurol.201131543344010.1055/s‑0031‑1299782 22266881
     [Google Scholar]
  25. BonifatiV. RohéC.F. BreedveldG.J. Early-onset parkinsonism associated with PINK1 mutations.Neurology2005651879510.1212/01.wnl.0000167546.39375.82 16009891
     [Google Scholar]
  26. NarendraD.P. YouleR.J. Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control.Antioxid. Redox Signal.201114101929193810.1089/ars.2010.3799 21194381
     [Google Scholar]
  27. PankratzN. PauciuloM.W. ElsaesserV.E. Mutations in DJ-1 are rare in familial Parkinson disease.Neurosci. Lett.2006408320921310.1016/j.neulet.2006.09.003 16997464
     [Google Scholar]
  28. SelvarajS. PiramanayagamS. Impact of gene mutation in the development of Parkinson’s disease.Genes Dis.20196212012810.1016/j.gendis.2019.01.004 31193965
     [Google Scholar]
  29. MacedoM.G. AnarB. BronnerI.F. The DJ-1L166P mutant protein associated with early onset Parkinson’s disease is unstable and forms higher-order protein complexes.Hum. Mol. Genet.200312212807281610.1093/hmg/ddg304 12952867
     [Google Scholar]
  30. ChaudharyS.S. ChaudharyS. RawatS. Chapter 5 - Recent developments in the etiology, treatment, and potential therapeutic targets for Parkinson’s disease: A focus on biochemistry.In: Diagnosis and Management in Parkinson’s Disease.Elsevier2020739010.1016/B978‑0‑12‑815946‑0.00005‑3
     [Google Scholar]
  31. MadureiraM. Connor-RobsonN. Wade-MartinsR. LRRK2: Autophagy and Lysosomal Activity.Front. Neurosci.20201449810.3389/fnins.2020.00498 32523507
     [Google Scholar]
  32. ToyofukuT. OkamotoY. IshikawaT. SasawatariS. KumanogohA. LRRK 2 regulates endoplasmic reticulum–mitochondrial tethering through the PERK‐mediated ubiquitination pathway.EMBO J.2020392e10087510.15252/embj.2018100875 31821596
     [Google Scholar]
  33. Estrada-CuzcanoA. MartinS. ChamovaT. Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78).Brain2017140228730510.1093/brain/aww307 28137957
     [Google Scholar]
  34. MerzettiE.M. StaveleyB.E. spargel, the PGC-1α homologue, in models of Parkinson disease in Drosophila melanogaster.BMC Neurosci.20151617010.1186/s12868‑015‑0210‑2 26502946
     [Google Scholar]
  35. WeissH.D. MarshL. Impulse control disorders and compulsive behaviors associated with dopaminergic therapies in Parkinson disease.Neurol. Clin. Pract.20122426727410.1212/CPJ.0b013e318278be9b 23634371
     [Google Scholar]
  36. ShinJ.H. KoH.S. KangH. PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson’s disease.Cell2011144568970210.1016/j.cell.2011.02.010 21376232
     [Google Scholar]
  37. DavidsonW.S. JonasA. ClaytonD.F. GeorgeJ.M. Stabilization of α-synuclein secondary structure upon binding to synthetic membranes.J. Biol. Chem.1998273169443944910.1074/jbc.273.16.9443 9545270
     [Google Scholar]
  38. El-AgnafO.M.A. JakesR. CurranM.D. Aggregates from mutant and wild‐type α‐synuclein proteins and NAC peptide induce apoptotic cell death in human neuroblastoma cells by formation of β‐sheet and amyloid‐like filaments.FEBS Lett.19984401-2717510.1016/S0014‑5793(98)01418‑5 9862428
     [Google Scholar]
  39. SpillantiniM.G. CrowtherR.A. JakesR. HasegawaM. GoedertM. α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies.Proc. Natl. Acad. Sci. USA199895116469647310.1073/pnas.95.11.6469 9600990
     [Google Scholar]
  40. De LorenzoA. AndreoliA. MatthieJ. WithersP. Predicting body cell mass with bioimpedance by using theoretical methods: A technological review.J. Appl. Physiol.19978251542155810.1152/jappl.1997.82.5.1542 9134904
     [Google Scholar]
  41. AbeliovichA. SchmitzY. FariñasI. Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system.Neuron200025123925210.1016/S0896‑6273(00)80886‑7 10707987
     [Google Scholar]
  42. ConwayK.A. LeeS.J. RochetJ.C. DingT.T. WilliamsonR.E. LansburyP.T. Acceleration of oligomerization, not fibrillization, is a shared property of both α-synuclein mutations linked to early-onset Parkinson’s disease: Implications for pathogenesis and therapy.Proc. Natl. Acad. Sci. USA200097257157610.1073/pnas.97.2.571 10639120
     [Google Scholar]
  43. KazantsevA.G. KolchinskyA.M. Central role of α-synuclein oligomers in neurodegeneration in Parkinson disease.Arch. Neurol.200865121577158110.1001/archneur.65.12.1577 19064744
     [Google Scholar]
  44. AuluckP.K. CaraveoG. LindquistS. α-Synuclein: membrane interactions and toxicity in Parkinson’s disease.Annu. Rev. Cell Dev. Biol.201026121123310.1146/annurev.cellbio.042308.113313 20500090
     [Google Scholar]
  45. BonifacinoJ.S. RojasR. Retrograde transport from endosomes to the trans-Golgi network.Nat. Rev. Mol. Cell Biol.20067856857910.1038/nrm1985 16936697
     [Google Scholar]
  46. Greten-HarrisonB. PolydoroM. Morimoto-TomitaM. αβγ-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction.Proc. Natl. Acad. Sci. USA201010745195731957810.1073/pnas.1005005107 20974939
     [Google Scholar]
  47. ChandraS. GallardoG. Fernández-ChacónR. SchlüterO.M. SüdhofT.C. α-synuclein cooperates with CSPalpha in preventing neurodegeneration.Cell2005123338339610.1016/j.cell.2005.09.028 16269331
     [Google Scholar]
  48. BurréJ. SharmaM. TsetsenisT. BuchmanV. EthertonM.R. SüdhofT.C. Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro.Science201032959991663166710.1126/science.1195227 20798282
     [Google Scholar]
  49. WoodS.J. WypychJ. SteavensonS. LouisJ.C. CitronM. BiereA.L. α-synuclein fibrillogenesis is nucleation-dependent. Implications for the pathogenesis of Parkinson’s disease.J. Biol. Chem.199927428195091951210.1074/jbc.274.28.19509 10391881
     [Google Scholar]
  50. SingletonA. Gwinn-HardyK. Parkinson’s disease and dementia with Lewy bodies: A difference in dose?Lancet200436494401105110710.1016/S0140‑6736(04)17117‑1 15451205
     [Google Scholar]
  51. WaxmanE.A. GiassonB.I. Molecular mechanisms of α-synuclein neurodegeneration.Biochim. Biophys. Acta Mol. Basis Dis.20091792761662410.1016/j.bbadis.2008.09.013 18955133
     [Google Scholar]
  52. SuX. FederoffH.J. Maguire-ZeissK.A. Mutant α-synuclein overexpression mediates early proinflammatory activity.Neurotox. Res.200916323825410.1007/s12640‑009‑9053‑x 19526281
     [Google Scholar]
  53. TheodoreS. CaoS. McLeanP.J. StandaertD.G. Targeted overexpression of human α-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease.J. Neuropathol. Exp. Neurol.200867121149115810.1097/NEN.0b013e31818e5e99 19018246
     [Google Scholar]
  54. CovyJ.P. GiassonB.I. α-Synuclein, leucine-rich repeat kinase-2, and manganese in the pathogenesis of parkinson disease.Neurotoxicology201132562262910.1016/j.neuro.2011.01.003 21238487
     [Google Scholar]
  55. FujiedaN. YabutaS. IkedaT. Crystal structures of copper-depleted and copper-bound fungal pro-tyrosinase: Insights into endogenous cysteine-dependent copper incorporation.J. Biol. Chem.201328830221282214010.1074/jbc.M113.477612 23749993
     [Google Scholar]
  56. WangX. LiuY. ChenH. LEF-1 Regulates tyrosinase gene transcription in vitro.PLoS One20151011e014314210.1371/journal.pone.0143142 26580798
     [Google Scholar]
  57. MoonH.R. YunH.Y. KimD.H. Design, synthesis, and] anti-melanogenic effects of (E)-2-benzoyl-3-(substituted phenyl)] acrylonitriles.Drug Des. Devel. Ther.20159Aug4259426810.2147/DDDT.S89976 26347064
     [Google Scholar]
  58. GreggioE. BergantinoE. CarterD. Tyrosinase exacerbates dopamine toxicity but is not genetically associated with Parkinson’s disease.J. Neurochem.200593124625610.1111/j.1471‑4159.2005.03019.x 15773923
     [Google Scholar]
  59. Carballo-CarbajalI. LagunaA. Romero-GiménezJ. Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson’s disease pathogenesis.Nat. Commun.201910197310.1038/s41467‑019‑08858‑y 30846695
     [Google Scholar]
  60. LiQ. MoJ. XiongB. Discovery of resorcinol-based polycyclic structures as tyrosinase inhibitors for treatment of Parkinson’s disease.ACS Chem. Neurosci.2022131819610.1021/acschemneuro.1c00560 34882402
     [Google Scholar]
  61. OyamaT. TakahashiS. YoshimoriA. Discovery of a new type of scaffold for the creation of novel tyrosinase inhibitors.Bioorg. Med. Chem.201624184509451510.1016/j.bmc.2016.07.060 27507110
     [Google Scholar]
  62. JanickaM. SztankeM. SztankeK. Predicting the blood-brain barrier permeability of new drug-like compounds via HPLC with various stationary phases.Molecules202025348710.3390/molecules25030487 31979316
     [Google Scholar]
  63. QiS. GuoL. LiangJ. A new strategy for the treatment of Parkinson’s disease: Discovery and bio-evaluation of the first central-targeting tyrosinase inhibitor.Bioorg. Chem.202415010761210.1016/j.bioorg.2024.107612 38986418
     [Google Scholar]
  64. DenyerR. DouglasM.R. Gene therapy for Parkinson’s disease.Parkinsons Dis.2012201211310.1155/2012/757305 22619738
     [Google Scholar]
  65. YasumotoK. YokoyamaK. TakahashiK. TomitaY. ShibaharaS. Functional analysis of microphthalmia-associated transcription factor in pigment cell-specific transcription of the human tyrosinase family genes.J. Biol. Chem.1997272150350910.1074/jbc.272.1.503 8995290
     [Google Scholar]
  66. ParkH.Y. WuC. YonemotoL. MITF mediates cAMP-induced protein kinase C-β expression in human melanocytes.Biochem. J.2006395357157810.1042/BJ20051388 16411896
     [Google Scholar]
  67. FangD. TsujiY. SetaluriV. Selective down-regulation of tyrosinase family gene TYRP1 by inhibition of the activity of melanocyte transcription factor, MITF.Nucleic Acids Res.200230143096310610.1093/nar/gkf424 12136092
     [Google Scholar]
  68. PriyadarshanP.M. Induced mutations and polyploidy breeding.In: PLANT BREEDING: Classical to Modern.SingaporeSpringer Singapore201932937010.1007/978‑981‑13‑7095‑3_16
     [Google Scholar]
  69. CareyH.A. OstrowskiM.C. SharmaS.M. Crystallizing the functional specificity of MITF.Pigment Cell Melanoma Res.201326215815910.1111/pcmr.12050
     [Google Scholar]
  70. ChunS.H. YukJ.S. UmS.H. Regulation of cellular gene expression by nanomaterials.Nano Converg.2018513410.1186/s40580‑018‑0166‑x 30499017
     [Google Scholar]
  71. NakashimaA. HayashiN. KanekoY.S. Role of N-terminus of tyrosine hydroxylase in the biosynthesis of catecholamines.J. Neural Transm. (Vienna)2009116111355136210.1007/s00702‑009‑0227‑8 19396395
     [Google Scholar]
  72. NagatsuT. NagatsuI. Tyrosine hydroxylase (TH), its cofactor tetrahydrobiopterin (BH4), other catecholamine-related enzymes, and their human genes in relation to the drug and gene therapies of Parkinson’s disease (PD): Historical overview and future prospects.J. Neural Transm. (Vienna)2016123111255127810.1007/s00702‑016‑1596‑4 27491309
     [Google Scholar]
  73. JohT.H. BaetgeE.E. RossM.E. ReisD.J. Biochemistry and molecular biology of catecholamine neurons: a single gene or gene family hypothesis.Clin. Exp. Hypertens. A198461-2112110.3109/10641968409062548 6141853
     [Google Scholar]
  74. PardridgeW.M. Tyrosine hydroxylase replacement in experimental Parkinson’s disease with transvascular gene therapy.NeuroRx20052112913810.1602/neurorx.2.1.129 15717064
     [Google Scholar]
  75. AxelsenT.M. WoldbyeD.P.D. Gene therapy for Parkinson’s disease, an update.J. Parkinsons Dis.20188219521510.3233/JPD‑181331 29710735
     [Google Scholar]
  76. ChenJ. GuoZ. TianH. ChenX. Production and clinical development of nanoparticles for gene delivery.Mol. Ther. Methods Clin. Dev.201631602310.1038/mtm.2016.23 27088105
     [Google Scholar]
  77. RenW. DuanS. DaiC. XieC. JiangL. ShiY. Nanotechnology lighting the way for gene therapy in ophthalmopathy: From opportunities toward applications.Molecules2023288350010.3390/molecules28083500 37110734
     [Google Scholar]
  78. MakadiaH.K. SiegelS.J. Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier.Polymers (Basel)2011331377139710.3390/polym3031377 22577513
     [Google Scholar]
  79. GuptaV. BhavanasiS. QuadirM. Protein PEGylation for cancer therapy: Bench to bedside.J. Cell Commun. Signal.201913331933010.1007/s12079‑018‑0492‑0 30499020
     [Google Scholar]
  80. ZhangY. SchlachetzkiF. ZhangY.F. BoadoR.J. PardridgeW.M. Normalization of striatal tyrosine hydroxylase and reversal of motor impairment in experimental parkinsonism with intravenous nonviral gene therapy and a brain-specific promoter.Hum. Gene Ther.200415433935010.1089/104303404322959498 15053859
     [Google Scholar]
  81. HerranzF. AlmarzaE. RodríguezI. The application of nanoparticles in gene therapy and magnetic resonance imaging.Microsc. Res. Tech.201174757759110.1002/jemt.20992 21484943
     [Google Scholar]
  82. DuanL. OuyangK. XuX. Nanoparticle delivery of CRISPR/Cas9 for genome editing.Front. Genet.20211267328610.3389/fgene.2021.673286 34054927
     [Google Scholar]
  83. FinnJ.D. SmithA.R. PatelM.C. A single administration of CRISPR/Cas9 lipid nanoparticles achieves robust and persistent in vivo genome editing.Cell Rep.20182292227223510.1016/j.celrep.2018.02.014 29490262
     [Google Scholar]
/content/journals/cnsnddt/10.2174/0118715273336139241211071748
Loading
Unravelling the Role of Tyrosine and Tyrosine Hydroxylase in Parkinson’s Disease: Exploring Nanoparticle-based Gene Therapies
CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) 24, 325 (2025); https://doi.org/10.2174/0118715273336139241211071748
/content/journals/cnsnddt/10.2174/0118715273336139241211071748
/content/journals/cnsnddt/10.2174/0118715273336139241211071748
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): CRISPR; drug delivery; gene regulation; gene silencing; gene therapy; nanoparticles; Neurodegeneration; Parkinson's disease

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test