Skip to main content

Advertisement

SpringerLink
Log in

Understanding multifactorial architecture of Parkinson’s disease: pathophysiology to management

  • Review Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

Parkinson’s disease (PD) is the second most common multifactorial neurodegenerative disorder affecting 3% of population during elder age. The loss of substantia nigra, pars compacta (SNpc) neurons and deficiency of striatal dopaminergic neurons produces stables motor deficient. Further, increase alpha-synuclein accumulation, mitochondrial dysfunction, oxidative stress, excitotoxicity, and neuroinflammation plays a crucial role in the pathogenesis of PD. Alpha-synuclein protein encodes for SNCA gene and disturbs the normal physiological neuronal signaling via altering mitochondrial homeostasis. The level of α-synuclein is increased in both normal aging and PD brain to a greater extent and secondly reduced clearance results in accumulation of Lewy bodies (LB). Emerging evidences indicate that mitochondrial dysfunction might be a common cause but pathological insult through protein misfolding, aggregation, and accumulation leads to neuronal apoptosis. The observation supporting that expression of DJ-1, LLRK2, PARKIN, PINK1, and excessive excitotoxicity mediated by dysbalance between GABA and glutamate reduced mitochondrial functioning and increased neurotoxicity. Therefore, the present review summarizes the various pathological mechanisms and also explores the therapeutic strategies which could be useful to ameliorate movement disorder like Parkinsonism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Błaszczyk JW (2016) Parkinson’s disease and neurodegeneration: GABA-collapse hypothesis. front. Neurosci 10:269 1–8

    Google Scholar 

  2. Magrinelli F, Picelli A, Tocco P, Federico A, Roncari L, Smania N, Zanette G, Tamburin S (2016) Pathophysiology of motor dysfunction in Parkinson’s disease as the rationale for drug treatment and rehabilitation. Park Dis 2016:1–18

    Google Scholar 

  3. Hirsch L, Jette N, Frolkis A, Steeves T, Pringsheim T (2016) The incidence of Parkinson’s disease: a systematic review and meta-analysis. Neuroepidemiology 46:292–300

    Article  PubMed  Google Scholar 

  4. Reeve A, Simcox E, Turnbull D (2014) Ageing and Parkinson’s disease: why is advancing age the biggest risk factor? Ageing Res Rev 14:19–30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gagnon D, Petryszyn S, Sanchez MG, Bories C, Beaulieu JM, De Koninck Y, Parent A, Parent M (2017) Striatal neurons expressing D1 and D2 receptors are morphologically distinct and differently affected by dopamine denervation in mice. Sci Rep 27(7):41432–41448

  6. Longhena F, Faustini G, Missale C, Pizzi M, Spano P, Bellucci A (2017) The contribution of α-synuclein spreading to Parkinson’s disease synaptopathy., neural Plast. 2017 5012129:1–15

    Google Scholar 

  7. Klein C, Westenberger A (2012) Genetics of Parkinson’s disease. Cold Spring Harb. Perspect. Med 2:a008888 1–15

    Article  PubMed  PubMed Central  Google Scholar 

  8. Phillipson OT (2017) Alpha-synuclein, epigenetics, mitochondria, metabolism, calcium traffic, & circadian dysfunction in Parkinson’s disease. An integrated strategy for management. Ageing Res Rev 40:149–167

    Article  CAS  PubMed  Google Scholar 

  9. Ihse E, Yamakado H, van Wijk XM, Lawrence R, Esko JD, Masliah E (2017) Cellular internalization of alpha-synuclein aggregates by cell surface heparan sulfate depends on aggregate conformation and cell type. Sci Rep 7:9008 1–10

    Article  PubMed  PubMed Central  Google Scholar 

  10. Siddiqui A, Chinta SJ, Mallajosyula JK, Rajagopolan S, Hanson I, Rane A, Melov S, Andersen JK (2012) Selective binding of nuclear alpha-synuclein to the PGC1alpha promoter under conditions of oxidative stress may contribute to losses in mitochondrial function: implications for Parkinson’s disease. Free Radic Biol Med 53:993–1003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dunn AR, Stout KA, Ozawa M, Lohr KM, Hoffman CA, Bernstein AI, Li Y, Wang M, Sgobio C, Sastry N, Cai H, Caudle WM, Miller GW (2017) Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease. Proc Natl Acad Sci U S A 114(11):2253–2262

  12. Li J, WO, Li W, Jiang Z-G, Ghanbari HA (2013) Oxidative stress and neurodegenerative disorders. Int J Mol Sci 14:24438–24475

    Article  PubMed  PubMed Central  Google Scholar 

  13. Philippart F, Destreel G, Merino-Sepulveda P, Henny P, Engel D, Seutin V (2016) Differential somatic Ca2+ channel profile in midbrain dopaminergic neurons. J Neurosci 36:7234–7245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. van Horssen J, van Schaik P, Witte M (2017) Inflammation and mitochondrial dysfunction: a vicious circle in neurodegenerative disorders? Neurosci Lett 3940(17):30542–30548

  15. Moon HE, Paek SH (2015) Mitochondrial dysfunction in Parkinson’s disease. Exp. Neurobiol 24:103–116

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ni H-M, Williams JA, Ding W-X (2015) Mitochondrial dynamics and mitochondrial quality control. Redox Biol 4:6–13

    Article  CAS  PubMed  Google Scholar 

  17. Nita M, Grzybowski A (2016) The role of the reactive oxygen species and oxidative stress in the pathomechanism of the age-related ocular diseases and other pathologies of the anterior and posterior eye segments in adults. Oxid. Med. Cell Longev 2016:3164734 1–23

    Article  PubMed  PubMed Central  Google Scholar 

  18. Kalogeris T, Bao Y, Korthuis RJ (2014) Mitochondrial reactive oxygen species: a double edged sword in ischemia/reperfusion vs preconditioning. Redox Biol 2:702–714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Camilleri A, Vassallo N (2014) The centrality of mitochondria in the pathogenesis and treatment of Parkinson’s disease. CNS Neurosci Ther 20:591–602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Subramaniam SR, Chesselet M-F (2013) Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Prog Neurobiol 106–107:17–32

    Article  PubMed  Google Scholar 

  21. Truban D, Hou X, Caulfield TR, Fiesel FC, Springer W (2017) PINK1, Parkin, and mitochondrial quality control: what can we learn about Parkinson’s disease pathobiology? J Parkinsons Dis 7:13–29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Arun S, Liu L, Donmez G (2016) Mitochondrial Biology and Neurological Diseases. Curr Neuropharmacol 14:143–154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bose A, Beal MF (2016) Mitochondrial dysfunction in Parkinson’s disease. J Neurochem 139:216–231

    Article  CAS  PubMed  Google Scholar 

  24. Hu Q, Wang G (2016) Mitochondrial dysfunction in Parkinson’s disease, Transl. Neurodegener 5:14 1–8

    Article  Google Scholar 

  25. Pickrell AM, Youle RJ (2015) The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron 85:257–273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhuang N, Li L, Chen S, Wang T (2016) PINK1-dependent phosphorylation of PINK1 and Parkin is essential for mitochondrial quality control. Cell Death Dis 7:e2501–e2501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Oh SE, Mouradian MM (2018) Cytoprotective mechanisms of DJ-1 against oxidative stress through modulating ERK1/2 and ASK1 signal transduction. Redox Biol 14:211–217

    Article  CAS  PubMed  Google Scholar 

  28. Cookson MR (2012) Parkinsonism due to mutations in PINK1, parkin, and DJ-1 and oxidative stress and mitochondrial pathways. Cold Spring Harb Perspect Med 2:a009415

    Article  PubMed  PubMed Central  Google Scholar 

  29. Luo Y, Hoffer AB, Qi X (2015) Mitochondria: a therapeutic target for Parkinson’s disease? Int J Mol Sci 16:20704–20730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rosenbusch KE, Kortholt A (2016) Activation mechanism of LRRK2 and its cellular functions in Parkinson’s disease. Park Dis 2016:1–8

    Google Scholar 

  31. Su X, Chu Y, Kordower JH, Li B, Cao H, Huang L, Nishida M, Song L, Wang D, Federoff HJ (2015) PGC−1α promoter methylation in Parkinson’s disease. PLoS One 10:e0134087

    Article  PubMed  PubMed Central  Google Scholar 

  32. Jiang H, Kang S-U, Zhang S, Karuppagounder S, Xu J, Lee Y-K, Kang B-G, Lee Y, Zhang J, Pletnikova O, Troncoso JC, Pirooznia S, Andrabi SA, Dawson VL, Dawson TM (2016) Adult conditional knockout of PGC-1 leads to loss of dopamine neurons. eNeuro 3(4):1–8

  33. Lee Y, Stevens DA, Kang S-U, Jiang H, Lee Y-I, Ko HS, Scarffe LA, Umanah GE, Kang H, Ham S, Kam T-I, Allen K, Brahmachari S, Kim JW, Neifert S, Yun SP, Fiesel FC, Springer W, Dawson VL, Shin J-H, Dawson TM (2017) PINK1 primes Parkin-mediated ubiquitination of PARIS in dopaminergic neuronal survival. Cell Rep 18:918–932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Vivekanantham S, Shah S, Dewji R, Dewji A, Khatri C, Ologunde R (2015) Neuroinflammation in Parkinson’s disease: role in neurodegeneration and tissue repair. Int J Neurosci 125:717–725

    Article  CAS  PubMed  Google Scholar 

  35. Shabab T, Khanabdali R, Moghadamtousi SZ, Kadir HA, Mohan G (2017) Neuroinflammation pathways: a general review. Int J Neurosci 127:624–633

    Article  CAS  PubMed  Google Scholar 

  36. Arcuri C, Mecca C, Bianchi R, Giambanco I, Donato R (2017) The pathophysiological role of microglia in dynamic surveillance, phagocytosis and structural remodeling of the developing CNS. Front. Mol. Neurosci 10:191 1–22

    Article  PubMed  PubMed Central  Google Scholar 

  37. Kawasaki T, Kawai T (2014) Toll-like receptor signaling pathways. Front. Immunol 5:461 1–8

    Article  PubMed  PubMed Central  Google Scholar 

  38. Lawrence T (2009) The nuclear factor NF-κB pathway in inflammation. Cold Spring Harb Perspect Biol 1(6):a001651

    Article  PubMed  PubMed Central  Google Scholar 

  39. Kaur K, Gill JS, Bansal PK, Deshmukh R (2017) Neuroinflammation - a major cause for striatal dopaminergic degeneration in Parkinson’s disease. J Neurol Sci 381:308–314

    Article  CAS  PubMed  Google Scholar 

  40. Wang Q, Liu Y, Zhou J (2012) Macroautophagy in sporadic and the genetic form of Parkinson’s disease with the A53T α-synuclein mutation. Transl Neurodegener 2012:1–7

  41. Le W, Wu J, Tang Y (2016) Protective microglia and their regulation in Parkinson’s disease. Front. Mol Neurosci 9:89 1–13

    Article  PubMed  PubMed Central  Google Scholar 

  42. Tang Y, Le W (2016) Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol 53:1181–1194

    Article  CAS  PubMed  Google Scholar 

  43. Morales I, Farías GA, Cortes N, Maccioni RB (2016) Neuroinflammation and neurodegeneration. In: Update dementia. InTech, pp 18–32

  44. Jäkel S, Dimou L (2017) Glial cells and their function in the adult brain: a journey through the history of their ablation. Front. Cell. Neurosci 11:24 1–17

    Article  PubMed  PubMed Central  Google Scholar 

  45. Booth HDE, Hirst WD, Wade-Martins R (2017) The role of astrocyte dysfunction in Parkinson’s disease pathogenesis. Trends Neurosci 40:358–370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hennessy E, Griffin ÉW, Cunningham C (2015) Astrocytes are primed by chronic neurodegeneration to produce exaggerated chemokine and cell infiltration responses to acute stimulation with the cytokines IL-1β and TNF-α. J Neurosci 35:8411–8422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tartey S, Takeuchi O (2017) Pathogen recognition and toll-like receptor targeted therapeutics in innate immune cells. Int Rev Immunol 36:57–73

    Article  CAS  PubMed  Google Scholar 

  48. Drouin-Ouellet J, St-Amour I, Saint-Pierre M, Lamontagne-Proulx J, Kriz J, Barker RA, Cicchetti F (2015) Toll-like receptor expression in the blood and brain of patients and a mouse model of Parkinson’s disease. Int J Neuropsychopharmacol 18(6):pyu103

    Article  PubMed Central  Google Scholar 

  49. Dzamko N, Gysbers A, Perera G, Bahar A, Shankar A, Gao J, Fu Y, Halliday GM (2017) Toll-like receptor 2 is increased in neurons in Parkinson’s disease brain and may contribute to alpha-synuclein pathology. Acta Neuropathol 133:303–319

    Article  CAS  PubMed  Google Scholar 

  50. Lawrence T (2009) The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 1:a001651

    Article  PubMed  PubMed Central  Google Scholar 

  51. Erreni M, Manfredi AA, Garlanda C, Mantovani A, Rovere-Querini P (2017) The long pentraxin PTX3: a prototypical sensor of tissue injury and a regulator of homeostasis. Immunol Rev 280:112–125

    Article  CAS  PubMed  Google Scholar 

  52. Taniguchi K, Karin M (2018) NF-κB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol 18:309–324

    Article  CAS  PubMed  Google Scholar 

  53. Wynne BM, Zou L, Linck V, Hoover RS, Ma H-P, Eaton DC (2017) Regulation of lung epithelial sodium channels by cytokines and chemokines. Front Immunol 8:766

    Article  PubMed  PubMed Central  Google Scholar 

  54. Varatharaj A, Galea I (2017) The blood-brain barrier in systemic inflammation. Brain Behav Immun 60:1–12

    Article  CAS  PubMed  Google Scholar 

  55. Jorgensen I, Rayamajhi M, Miao EA (2017) Programmed cell death as a defence against infection. Nat. Rev. Immunol. 17:151–164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ribeiro FM, Vieira LB, Pires RGW, Olmo RP, Ferguson SSG (2017) Metabotropic glutamate receptors and neurodegenerative diseases. Pharmacol Res 115:179–191

    Article  CAS  PubMed  Google Scholar 

  57. Zhang Y, Tan F, Xu P, Qu S (2016) Recent advance in the relationship between excitatory amino acid transporters and Parkinson’s disease. Neural Plast 2016:1–8

    Google Scholar 

  58. Jinsmaa Y, Florang VR, Rees JN, Mexas LM, Eckert LL, Allen EMG, Anderson DG, Doorn JA (2011) Dopamine-derived biological reactive intermediates and protein modifications: implications for Parkinson’s disease. Chem Biol Interact 192:118–121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kim GH, Kim JE, Rhie SJ, Yoon S (2015) The role of oxidative stress in neurodegenerative diseases. Exp Neurobiol 24:325–340

    Article  PubMed  PubMed Central  Google Scholar 

  60. Sifuentes-Franco S, Pacheco-Moisés FP, Rodríguez-Carrizalez AD, Miranda-Díaz AG (2017) The role of oxidative stress, mitochondrial function, and autophagy in diabetic polyneuropathy. J Diabetes Res 2017:1673081

    Article  PubMed  PubMed Central  Google Scholar 

  61. Dias V, Junn E, Mouradian MM (2013) The role of oxidative stress in Parkinson’s disease. J Parkinsons Dis 3:461–491

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Zaichick SV, McGrath KM, Caraveo G (2017) The role of Ca2+signaling in Parkinson’s disease. Dis Model Mech 10:519–535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Setya S, Madaan T, Tariq M, Razdan BK, Talegaonkar S (2018) Appraisal of transdermal water-in-oil nanoemulgel of selegiline HCl for the effective management of Parkinson’s disease: pharmacodynamic, pharmacokinetic, and biochemical investigations. AAPS PharmSciTech 19:573–589

    Article  CAS  PubMed  Google Scholar 

  64. Yu W, Chen S, Cao L, Tang J, Xiao W, Xiao B (2017) Ginkgolide K promotes the clearance of A53T mutation alpha-synuclein in SH-SY5Y cells. Cell Biol Toxicol 34(4):291–303

  65. Pineda A, Burré J (2017) Modulating membrane binding of α-synuclein as a therapeutic strategy. Proc Natl Acad Sci U S A 114:1223–1225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hu G, Gong X, Wang L, Liu M, Liu Y, Fu X, Wang W, Zhang T, Wang X (2017) Triptolide promotes the clearance of α-synuclein by enhancing autophagy in neuronal cells. Mol Neurobiol 54:2361–2372

    Article  CAS  PubMed  Google Scholar 

  67. de Ceballos ML (2015) Cannabinoids for the treatment of neuroinflammation. Cannabinoids in Neurologic Mental Disease, pp 3–14. https://doi.org/10.1016/B978-0-12-417041-4.00001-1

  68. Ghosh A, Langley MR, Harischandra DS, Neal ML, Jin H, Anantharam V, Joseph J, Brenza T, Narasimhan B, Kanthasamy A, Kalyanaraman B, Kanthasamy AG (2016) Mitoapocynin treatment protects against neuroinflammation and dopaminergic neurodegeneration in a preclinical animal model of Parkinson’s disease. J NeuroImmune Pharmacol 11:259–278

    Article  PubMed  PubMed Central  Google Scholar 

  69. Ay M, Luo J, Langley M, Jin H, Anantharam V, Kanthasamy A, Kanthasamy AG (2017) Molecular mechanisms underlying protective effects of quercetin against mitochondrial dysfunction and progressive dopaminergic neurodegeneration in cell culture and MitoPark transgenic mouse models of Parkinson’s disease. J Neurochem 141:766–782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Yu Y, Yang M, Chen R, Chen H (2017) Observation on the curative effect of madopar combined with pramipexole in the treatment of Parkinson’s diseases. Adv Emerg Med 1(6):1–13

  71. Cereda E, Cilia R, Canesi M, Tesei S, Mariani CB, Zecchinelli AL, Pezzoli G (2017) Efficacy of rasagiline and selegiline in Parkinson’s disease: a head-to-head 3-year retrospective case-control study. J Neurol 264:1254–1263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors are highly thankful to Dr. Shamsher Singh, Associate professor, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India for providing support and keen guidance.

Author information

Authors and Affiliations

  1. Neuroscience Division, Department of Pharmacology, Indo-Soviet Friendship College of Pharmacy, Moga, Punjab, India

    Ramandeep Kaur, Sidharth Mehan & Shamsher Singh

Authors
  1. Ramandeep Kaur
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sidharth Mehan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shamsher Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shamsher Singh.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kaur, R., Mehan, S. & Singh, S. Understanding multifactorial architecture of Parkinson’s disease: pathophysiology to management. Neurol Sci 40, 13–23 (2019). https://doi.org/10.1007/s10072-018-3585-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-018-3585-x

Keywords

Search

Navigation