Skip to content
2000
Volume 20, Issue 3
  • ISSN: 1574-3624
  • E-ISSN: 2212-389X

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms such as tremors, stiffness, and bradykinesia, as well as non-motor symptoms like cognitive impairment and mood swings. PD is a multifactorial disease comprised of environmental and genetic etiologies. In addition to family history, Variants in the gene are important as they represent the most common cause of familial PD and are also associated with some sporadic cases. The underlying causes of PD are also numerous and can be divided into a variety of environmental and genetic factors. This is the most relevant part because the gene Variant is one of the most common causes of familial Parkinson's disease, as well as contributing to sporadic cases beyond hereditary factors. Pathogenic variants result in the dysfunction of , disrupting cellular pathways and potentially driving neurodegeneration. The purpose of the current study was to examine in depth the complex network of -regulated signalling pathways and how they collectively modulate changes in neuronal survival and function. These variants are causing cell homeostasis disturbances due to dysfunction of interaction between key proteins such as α-synuclein and tau that have been implicated in Parkinson's development. In addition, we will explore what other therapies could be targeted to mitigate the role of -mediated processes in PD, such as kinase inhibitors and other process-targeted treatments.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cst/10.2174/0115743624360618250507112532
2025-05-14
2025-10-11

  • From This Site

    /content/journals/cst/10.2174/0115743624360618250507112532
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. RaniK. MukherjeeR. SinghE. Neuronal exosomes in saliva of Parkinson’s disease patients: A pilot study.Parkinsonism Relat. Disord.201967212310.1016/j.parkreldis.2019.09.008 31621600
     [Google Scholar]
  2. HendersonM.X. SenguptaM. TrojanowskiJ.Q. LeeV.M.Y. Alzheimer’s disease tau is a prominent pathology in LRRK2 Parkinson’s disease.Acta Neuropathol. Commun.20197118310.1186/s40478‑019‑0836‑x 31733655
     [Google Scholar]
  3. PoeweW. BaroneP. GliadiN. GilmanS. LowP.A. SampaioC. A randomized, placebo-controlled clinical trail to assess the effects of rasagiline in patients with multiple system atrophy of the parkinsonian subtype.Mov. Disord.201220121182
     [Google Scholar]
  4. Launch of WHO’s Parkinson disease technical brief2022Available from: https://www.who.int/news/item/14-06-2022-launch-of-who-s-parkinson-disease-technical-brief
  5. RademacherK. NakamuraK. Role of dopamine neuron activity in Parkinson’s disease pathophysiology.Exp. Neurol.202437311464510.1016/j.expneurol.2023.114645 38092187
     [Google Scholar]
  6. MunhozRP TumasV PedrosoJL Silveira-MoriyamaL The clinical diagnosis of Parkinson’s disease.Arq Neuropsiquiatr20248260011010.1055/s‑0043‑1777775 38325391
     [Google Scholar]
  7. SainiN. SinghN. KaurN. Motor and non-motor symptoms, drugs, and their mode of action in Parkinson’s disease (PD): A review.Med. Chem. Res.202433458059910.1007/s00044‑024‑03203‑5
     [Google Scholar]
  8. AlharbiB. Al-kuraishyH.M. Al-GareebA.I. Role of GABA pathway in motor and non-motor symptoms in Parkinson’s disease: A bidirectional circuit.Eur. J. Med. Res.202429120510.1186/s40001‑024‑01779‑7 38539252
     [Google Scholar]
  9. ItoG. Utsunomiya-TateN. Overview of the impact of pathogenic LRRK2 mutations in Parkinson’s disease.Biomolecules202313584510.3390/biom13050845 37238714
     [Google Scholar]
  10. LamaA. PirozziC. AvaglianoC. Nutraceuticals: An integrative approach to starve Parkinson’s disease.Brain Behav. Immun. Health2020210003710.1016/j.bbih.2020.100037 34589828
     [Google Scholar]
  11. HöglingerG. BährM. BecktepeJ. Diagnosis and treatment of Parkinson’s disease (guideline of the German Society for Neurology).Neurol. Res. Pract.2024613010.1186/s42466‑024‑00325‑4 38845028
     [Google Scholar]
  12. 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]
  13. KleinC. WestenbergerA. Genetics of Parkinson’s disease.Cold Spring Harb. Perspect. Med.201221a00888810.1101/cshperspect.a008888 22315721
     [Google Scholar]
  14. GialluisiA. RecciaM.G. ModugnoN. Identification of sixteen novel candidate genes for late onset Parkinson’s disease.Mol. Neurodegener.20211613510.1186/s13024‑021‑00455‑2 34148545
     [Google Scholar]
  15. 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]
  16. PringsheimT. JetteN. FrolkisA. SteevesT.D.L. The prevalence of Parkinson’s disease: A systematic review and meta‐analysis.Mov. Disord.201429131583159010.1002/mds.25945 24976103
     [Google Scholar]
  17. HansenC. LiJ.Y. Beyond α-synuclein transfer: Pathology propagation in Parkinson’s disease.Trends Mol. Med.201218524825510.1016/j.molmed.2012.03.002 22503115
     [Google Scholar]
  18. KimJ.J. VitaleD. OtaniD.V. Multi-ancestry genome-wide association meta-analysis of Parkinson’s disease.Nat. Genet.2024561273610.1038/s41588‑023‑01584‑8 38155330
     [Google Scholar]
  19. JeongG.R. LeeB.D. Pathological functions of LRRK2 in Parkinson’s disease.Cells2020912256510.3390/cells9122565 33266247
     [Google Scholar]
  20. LangA.E. ObesoJ.A. Challenges in Parkinson’s disease: Restoration of the nigrostriatal dopamine system is not enough.Lancet Neurol.20043530931610.1016/S1474‑4422(04)00740‑9 15099546
     [Google Scholar]
  21. KingwellK. LRRK2-targeted Parkinson disease drug advances into phase III.Nat. Rev. Drug Discov.20232213510.1038/d41573‑022‑00212‑0 36509915
     [Google Scholar]
  22. DorseyE.R. ElbazA. NicholsE. Global, regional, and national burden of Parkinson’s disease, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016.Lancet Neurol.2018171193995310.1016/S1474‑4422(18)30295‑3 30287051
     [Google Scholar]
  23. de RijkM.C. BretelerM.M.B. GravelandG.A. Prevalence of Parkinson’s disease in the elderly.Neurology199545122143214610.1212/WNL.45.12.2143 8848182
     [Google Scholar]
  24. LeongY.Q. KohR.Y. ChyeS.M. NgK.Y. Unravelling the genetic links between Parkinson’s disease and lung cancer.Biol. Chem.2023404655156710.1515/hsz‑2022‑0228 36634094
     [Google Scholar]
  25. ZhaoB. Natural antioxidants protect neurons in Alzheimer’s disease and Parkinson’s disease.Neurochem. Res.200934463063810.1007/s11064‑008‑9900‑9 19125328
     [Google Scholar]
  26. WallingsR.L. TanseyM.G. LRRK2 regulation of immune-pathways and inflammatory disease.Biochem. Soc. Trans.20194761581159510.1042/BST20180463 31769472
     [Google Scholar]
  27. CooksonM.R. LRRK2 pathways leading to neurodegeneration.Curr. Neurol. Neurosci. Rep.20151574210.1007/s11910‑015‑0564‑y 26008812
     [Google Scholar]
  28. WallingsR. ManzoniC. BandopadhyayR. Cellular processes associated with LRRK 2 function and dysfunction.FEBS J.2015282152806282610.1111/febs.13305 25899482
     [Google Scholar]
  29. PajarilloE. RizorA. LeeJ. AschnerM. LeeE. The role of posttranslational modifications of α-synuclein and LRRK2 in Parkinson’s disease: Potential contributions of environmental factors.Biochim. Biophys. Acta Mol. Basis Dis.2019186581992200010.1016/j.bbadis.2018.11.017 30481588
     [Google Scholar]
  30. OunA. Sabogal-GuaquetaA.M. GaluhS. AlexanderA. KortholtA. DolgaA.M. The multifaceted role of LRRK2 in Parkinson’s disease: From human iPSC to organoids.Neurobiol. Dis.202217310583710.1016/j.nbd.2022.105837 35963526
     [Google Scholar]
  31. JacksonL.M. WoodruffB.K. TremblayC. Parkinson’s disease associated with G2019S LRRK2 mutations without lewy body pathology.Mov. Disord. Clin. Pract.202411787487810.1002/mdc3.14068 38757351
     [Google Scholar]
  32. HendersonM.X. CornblathE.J. LiH.L. ChangolkarL. ZhangB. BrownH.J. Tau pathology spreads between anatomically-connected regions of the brain and is modulated by a LRRK2 mutation.bioRxiv20202020.10.13.33785710.1101/2020.10.13.337857v1
     [Google Scholar]
  33. RideoutH.J. Chartier-HarlinM.C. FellM.J. The current state-of-the art of LRRK2-based biomarker assay development in Parkinson’s disease.Front. Neurosci.20201486510.3389/fnins.2020.00865 33013290
     [Google Scholar]
  34. TaymansJ.M. FellM. GreenamyreT. Perspective on the current state of the LRRK2 field.NPJ Parkinsons Dis.20239110410.1038/s41531‑023‑00544‑7 37393318
     [Google Scholar]
  35. BonamS.R. TranchantC. MullerS. Autophagy-lysosomal pathway as potential therapeutic target in Parkinson’s disease.Cells202110354710.3390/cells10123547
     [Google Scholar]
  36. KaliaL.V. LangA.E. HazratiL.N. Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease.JAMA Neurol.201572110010510.1001/jamaneurol.2014.2704 25401511
     [Google Scholar]
  37. BensimonG. LudolphA. AgidY. VidailhetM. PayanC. LeighP.N. Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: The NNIPPS Study.Brain2009132115617110.1093/brain/awn291 19029129
     [Google Scholar]
  38. GuiY. LiuH. ZhangL. LvW. HuX. Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease.Oncotarget2015635370433705310.18632/oncotarget.6158 26497684
     [Google Scholar]
  39. GetchellK. Promising disease-modifying therapies in Parkinson disease.Neurology Live2023
     [Google Scholar]
  40. ZhuH. HixsonP. MaW. SunJ. Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM.Cell Discov.20241011010.1038/s41421‑023‑00639‑8 38263358
     [Google Scholar]
  41. HuB. FangH. HuangZ. HuangW. HuangL. LiuH. An upconversion nanoplatform based multi-effective theatment for Parkinson’s disease.Chem. Eng. J.202346514295910.1016/j.cej.2023.142959
     [Google Scholar]
  42. BreydoL. WuJ.W. UverskyV.N. α-Synuclein misfolding and Parkinson’s disease. Biochim Biophys Acta (BBA) -.Mol Basis Dis201218222261285
     [Google Scholar]
  43. EserP. KocabicakE. BekarA. TemelY. Insights into neuroinflammatory mechanisms of deep brain stimulation in Parkinson’s disease.Exp. Neurol.202437411468410.1016/j.expneurol.2024.114684 38199508
     [Google Scholar]
  44. CerriS. MusL. BlandiniF. Parkinson’s disease in women and men: What’s the difference?J. Parkinsons Dis.20199350151510.3233/JPD‑191683 31282427
     [Google Scholar]
  45. SmythC. AnjumM.F. RaviS. DenisonT. StarrP. LittleS. Adaptive deep brain stimulation for sleep stage targeting in Parkinson’s disease.Brain Stimul.20231651292129610.1016/j.brs.2023.08.006 37567463
     [Google Scholar]
  46. JiaoF. MengL. DuK. LiX. The autophagy–lysosome pathway: A potential target in the chemical and gene therapeutic strategies for Parkinson’s disease.Neural Regen. Res.202520113915810.4103/NRR.NRR‑D‑23‑01195 38767483
     [Google Scholar]
  47. MengL. LiY. LiuC. Islet amyloid polypeptide triggers α-synuclein pathology in Parkinson’s disease.Prog. Neurobiol.202322610246210.1016/j.pneurobio.2023.102462 37150314
     [Google Scholar]
  48. XiaoB. TanE.K. Targeting α-synuclein and c-Abl in Parkinson’s disease.Trends Mol. Med.2023291188388510.1016/j.molmed.2023.07.004
     [Google Scholar]
  49. HalagaliP. TippavajhalaV.K. RathnanandM. SharmaH. PathakR. Inulin as a natural ingredient in cosmetics and personal care products BT. AkramW. MishraN. HaiderT. Inulin for Pharmaceutical Applications: A Versatile Biopolymer.SingaporeSpringer Nature Singapore202513714610.1007/978‑981‑97‑9056‑2_7
     [Google Scholar]
  50. HalagaliP. NayakD. TippavajhalaV.K. RathnanandM. BiswasD. SharmaH. Chapter 16 -Navigating the nanoscopic frontier: Ethical dimensions in developing nanocarriers for neurodegenerative diseases.The Neurodegeneration RevolutionEmerging Therapies and Sustainable Solutions.Academic Press202539942010.1016/B978‑0‑443‑28822‑7.00011‑8
     [Google Scholar]
  51. HalagaliP. NayakD. RathnanandM. TippavajhalaV.K. SharmaH. BiswasD. Chapter 15 - Synergizing sustainable green nanotechnology and AI/ML for advanced nanocarriers: A paradigm shift in the treatment of neurodegenerative diseases.The Neurodegeneration Revolution, Emerging Therapies and Sustainable Solutions.Academic Press202537339710.1016/B978‑0‑443‑28822‑7.00017‑9
     [Google Scholar]
  52. DattaD. ColacoV. BandiS.P. SharmaH. DhasN. GiramP.S. Classes/types of polymers used in oral delivery (natural, semisynthetic, synthetic), their chemical structure and general functionalities.Polymers for Oral Drug Delivery Technologies.Elsevier Science Ltd202526333310.1016/B978‑0‑443‑13774‑7.00007‑4
     [Google Scholar]
  53. SharmaH AnandA HalagaliP Advancement of nanoengineered flavonoids for chronic metabolic diseases.Role of flavonoids in chronic metabolic diseases202445951010.1002/9781394238071.ch13
     [Google Scholar]
  54. SharmaH. RachamallaH.K. MishraN. ChandraP. PathakR. AshiqueS. Introduction to exosome and its role in brain disorders.Exosomes Based Drug Delivery Strategies for Brain Disorders.SingaporeSpringer Nature Singapore202413510.1007/978‑981‑99‑8373‑5_1
     [Google Scholar]
  55. SharmaH. TyagiS.J. ChandraP. VermaA. KumarP. AshiqueS. Role of exosomes in Parkinson’s and Alzheimer’s diseases.Exosomes Based Drug Delivery Strategies for Brain Disorders.SingaporeSpringer Nature Singapore202414718210.1007/978‑981‑99‑8373‑5_6
     [Google Scholar]
  56. KumarP. SharmaH. SinghA. PandeyS.N. ChandraP. Correlation between exosomes and neuro-inflammation in various brain disorders.Exosomes Based Drug Delivery Strategies for Brain Disorders.SingaporeSpringer Nature Singapore202427330210.1007/978‑981‑99‑8373‑5_11
     [Google Scholar]
  57. Al NomanA. Dev SharmaP. Jahin MimT. Al AzadM. SharmaH. Molecular docking and ADMET analysis of coenzyme Q10 as a potential therapeutic agent for Alzheimer’s disease.Aging Pathobiol. Ther.20246411310.31491/APT.2024.12.155
     [Google Scholar]
  58. InamdarA. GurupadayyaB. HalagaliP. Unraveling neurological drug delivery: Polymeric nanocarriers for enhanced blood-brain barrier penetration.Curr. Drug Targets202526424326610.2174/0113894501339455241101065040 39513304
     [Google Scholar]
  59. MishraR. KaurV. NogaiL. Emerging insights and novel therapeutics in polycystic ovary syndrome.Biochem. Cell. Arch.20242421613162610.51470/bca.2024.24.2.1613
     [Google Scholar]
  60. InamdarA. GurupadayyaB. HalagaliP. Cutting-edge strategies for overcoming therapeutic barriers in Alzheimer’s disease.Curr. Pharm. Des.202431859861810.2174/0113816128344571241018154506 39492772
     [Google Scholar]
  61. Al NomanA. AfrosaH. LihuI.K. Vitamin D and neurological health: Unraveling risk factors, disease progression, and treatment potential.CNS Neurol. Disord. Drug Targets20242411210.2174/0118715273330972241009092828 39440730
     [Google Scholar]
  62. SarkarS. BhuiU. KumarB. Correlation between cognitive impairment and peripheral biomarkers - Significance of phosphorylated tau and amyloid-β in Alzheimer’s disease: A new insight.Curr. Psychiatry Res. Rev.20242112510.2174/0126660822329981241007105405
     [Google Scholar]
  63. ChandraP. SharmaH. Phosphodiesterase inhibitors for treatment of Alzheimer’s disease.Indian Drugs202461772210.53879/id.61.07.14382
     [Google Scholar]
  64. SharmaH. PathakR. BiswasD. Unveiling the therapeutic potential of modern probiotics in addressing neurodegenerative disorders: A comprehensive exploration, review and future perspectives on intervention strategies.Curr. Psychiatry Res. Rev.2025212e29042e2951010.2174/0126660822304321240520075036
     [Google Scholar]
  65. PathakR. KaurV. SharmaS. BhandariM. MishraR. SaxenaA. Pazopanib: Effective monotherapy for precise cancer treatment, targeting specific mutations and tumors.AfrJBioSc2024691311133010.33472/AFJBS.6.9.2024.1311‑1330
     [Google Scholar]
  66. KapoorD.U. SharmaH. MaheshwariR. Konjac glucomannan: A comprehensive review of its extraction, health benefits, and pharmaceutical applications.Carbohydr. Polym.202433912226610.1016/j.carbpol.2024.122266 38823930
     [Google Scholar]
  67. ChandraP. AliZ. FatimaN. SharmaH. SachanN. SharmaK.K. Shankhpushpi (Convolvulus pluricaulis): Exploring its cognitive enhancing mechanisms and therapeutic potential in neurodegenerative disorders.Curr. Bioact. Compd.20242010.2174/0115734072292339240416095600
     [Google Scholar]
  68. SharmaH. PathakR. KumarN. Endocannabinoid system: Role in depression, recompense, and pain control.J Surv Fish Sci2023104S2743275110.17762/sfs.v10i4S.1655
     [Google Scholar]
  69. SharmaH. KaushikM. GoswamiP. Role of miRNAs in brain development.MicroRNA20241329610910.2174/0122115366287127240322054519 38571343
     [Google Scholar]
  70. AshiqueS. PalR. SharmaH. MishraN. GargA. Unraveling the emerging niche role of extracellular vesicles (EVs) in traumatic brain injury (TBI).CNS Neurol. Disord. Drug Targets202423111357137010.2174/0118715273288155240201065041 38351688
     [Google Scholar]
  71. MehdiR.S. Quality by design (QBD) approach in processing of nanoparticles loading antifungal drugs.J. Coast. Life Med.2023111279290
     [Google Scholar]
  72. NayakD. ShettyM.M. HalagaliP. Formulation, optimization and evaluation of ibuprofen loaded menthosomes for transdermal delivery.Int. J. Pharm.202466512467110.1016/j.ijpharm.2024.124671 39245088
     [Google Scholar]
/content/journals/cst/10.2174/0115743624360618250507112532
Loading
Unravelling LRRK2 Pathways in Parkinson's Disease: Mechanisms and Intricacies
Current Signal Transduction Therapy 20, E15743624360618 (2025); https://doi.org/10.2174/0115743624360618250507112532
/content/journals/cst/10.2174/0115743624360618250507112532
/content/journals/cst/10.2174/0115743624360618250507112532
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): autophagy; cytoskeletal dynamics; kinase inhibitors; Neurodegeneration; vesicle trafficking; α-synuclein

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