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Sikora, J. Zinc Dyshomeostasis and Parkinson’s Disease. Encyclopedia. Available online: https://encyclopedia.pub/entry/9865 (accessed on 03 May 2024).
Sikora J. Zinc Dyshomeostasis and Parkinson’s Disease. Encyclopedia. Available at: https://encyclopedia.pub/entry/9865. Accessed May 03, 2024.
Sikora, Joanna. "Zinc Dyshomeostasis and Parkinson’s Disease" Encyclopedia, https://encyclopedia.pub/entry/9865 (accessed May 03, 2024).
Sikora, J. (2021, May 19). Zinc Dyshomeostasis and Parkinson’s Disease. In Encyclopedia. https://encyclopedia.pub/entry/9865
Sikora, Joanna. "Zinc Dyshomeostasis and Parkinson’s Disease." Encyclopedia. Web. 19 May, 2021.
Zinc Dyshomeostasis and Parkinson’s Disease
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This entry is adapted from the peer-reviewed paper 10.3390/ijms22094724

Zinc and other heavy metals have received considerable attention in neurodegenerative diseases because of their cytotoxicity. The role of zinc in the pathogenesis of PD is not straightforward because of its numerous and complex function. Both deficiency and excess of zinc have been incriminated in the development of the disease, though overwhelming evidence favor the later mechanism.

synaptic zinc Parkinson’s disease

1. Zinc Deficiency and Parkinson’s Disease

Several studies have examined whether plasma and CSF zinc levels are altered in PD patients. The reported data are, however, disparate. In some studies, circulating zinc levels were lower in PD patients [1][2][3][4][5][6][7][8], while in others they were normal or even increased [9][10][11][12][13][14][15]. Recent meta-analysis studies, though, point to lower zinc levels in serum and plasma and CSF of PD patients compared to healthy controls [16][17]. Findings from epidemiological studies examining the association of dietary intake of zinc and PD are also contradictory. Higher intake of zinc was associated with reduced risk of PD in some studies [18], but negative findings were reported by others [19][20]. The association between lower levels of circulating zinc and PD has been explained by its antioxidant role since this trace element is essential for a variety of enzymes and proteins (superoxide dismutase oxidative, metallothioneins, and interleukins) involved in oxidative stress and inflammation [21]. In support of this view, animal studies showed that exogenous zinc can produce its beneficial effects by multiple mechanisms. In vitro, zinc inhibits 6-OHDA-induced oxidative stress [22] and reduces methamphetamine-induced dopaminergic neurotoxicity by the increasing expression of metallothioneins, which in turn prevent the generation of reactive oxygen species [23][24]. Zinc treatment also reduces α-synuclein (α-syn), the predominant component of Lewy bodies, induced by methamphetamine in cell culture [25]. Finally, zinc deficiency has been suggested to lead to dysfunction of PARK2 (E3 ligase) that possesses zinc-binding domains. PARK2 binds eight zinc ions and the removal of zinc causes a near-complete unfolding of the protein and, thereby, loss of its function [26]. Accordingly, supplementation with zinc has been shown to increase lifespan, as well as motor function in the parkin KO Drosophila model of PD [27].

2. Zinc Excess and Parkinson’s Disease

There is an overwhelming body of evidence implicating an excess of ionic Zn2+ in dopaminergic neurodegeneration associated with PD. Zinc exposure has been identified as an environmental risk factor for PD [28] and post-mortem studies revealed excessive zinc depositions in the substantia nigra (SN) and the striatum of patients with idiopathic PD [10][29][30][31][32]. In line with these observations, in vitro and in vivo experiments with animal models of PD showed that cytosolic accumulation labile zinc is a hallmark of degenerating dopaminergic neurons [33][34][35][36][37][38][39]. Importantly, treatments with intracellular zinc chelators prevent neurodegeneration caused by many neurotoxins (6-OHDA, MPTP, and paraquat) confirming that cytosolic Zn2+ accumulation contributes to dopaminergic neuronal loss [40][41][42]. The mechanisms responsible for Zn2+ accumulation in the SN of PD patients are poorly understood. One possible cause could be a failure of the intracellular mechanisms that maintain Zn2+ homeostasis. In this respect, the human PARK9 (ATP13A2), a lysosomal type 5 P-type ATPase associated with autosomal recessive early-onset PD, has been shown to act as a transporter for lysosomal sequestration of cytoplasmic zinc [43][44][45]. In vitro, loss of PARK9 function causes an imbalance of zinc intracellular homeostasis that in turn leads to lysosomal impairment, accumulation of α-syn, and mitochondrial dysfunction [43][44][45].

More recently, Tamano and colleagues showed that increased cytosolic levels of toxic Zn2+ can also be caused by the influx of extracellular zinc into dopaminergic neurons [36][37][38]. In brain slices, both 6-OHDA and paraquat have been found to rapidly increase intracellular Zn2+ levels only in the SNc. The increase in intracellular Zn2+ concentrations was linked to the entry of extracellular Zn2+ through AMPA receptors because it could be blocked by CaEDTA and by an AMPA receptor antagonist (CNQX). Furthermore, combined infusions of intracellular Zn2+ chelators (ZnAF-2DA, TPEN) and 6-OHDA or paraquat into the SNc reduce the loss of nigrostriatal dopaminergic neurons and the associated motor deficits in rats.

While the above studies implicate dyshomeostasis of intracellular Zn2+ pool in dopaminergic cell loss, several studies showed that systemic or intra-nigral injections of exogenous zinc can, on its own, produce dopaminergic neurotoxicity [33][34][46][47][48]. For instance, chronic injections of zinc systemically cause degeneration of the nigrostriatal dopaminergic pathway and locomotor deficits in rats like the pesticide, paraquat [49][50][51]. Zinc treatment causes cellular dysfunction by increasing oxidative stress through activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and depletion of glutathione (GSH), which in turn trigger the apoptotic machinery leading to neuronal loss, as seen following paraquat treatment [33]. The motor deficits and dopaminergic cell neurodegeneration induced by chronic zinc treatments were also shown to involve activation of microglial cells and expression of inflammatory mediators (e.g., TNF-α, IL-1β) [52][53].

Viewed together, the evidence suggests that endogenous Zn2+ is a key actor in the pathophysiology of PD. However, the role of this cation seems highly complex as both beneficial and deleterious actions of intracellular Zn2+ have been implicated in PD. Beneficial actions have been linked to Zn2+ role in protection against oxidative stress by influencing the activity of antioxidant enzymes and signaling pathways, while deleterious actions have been attributed to generation of oxidative stress caused by intracellular Zn2+ overload. Besides alterations of intracellular zinc pools, emerging evidence now suggests that dysfunction of synaptic Zn2+ signaling may also contribute to PD.

References

  1. Ahmed, S.; Santosh, W. Metallomic profiling and linkage map analysis of early parkinson’s disease: A new insight to aluminum marker for the possible diagnosis. PLoS ONE 2010, 5.
  2. Alimonti, A.; Ristori, G.; Giubilei, F.; Stazi, M.; Pino, A.; Visconti, A.; Brescianini, S.; Monti, M.; Forte, G.; Stanzione, P.; et al. Serum chemical elements and oxidative status in Alzheimer’s disease, Parkinson disease and multiple sclerosis. Neurotoxicology 2007, 28, 450–456.
  3. Brewer, G.; Kanzer, S.; Zimmerman, E.; Molho, E.; Celmins, D.; Heckman, S.; Dick, R. Subclinical zinc deficiency in Alzheimer’s disease and Parkinson’s disease. Am. J. Alzheimers Dis. Other Demen. 2010, 25, 572–575.
  4. Hegde, M.; Shanmugavelu, P.; Vengamma, B.; Rao, T.; Menon, R.; Rao, R.; Rao, K. Serum trace element levels and the complexity of inter-element relations in patients with Parkinson’s disease. J. Trace Elem. Med. Biol. 2004, 18, 163–171.
  5. Jiménez-Jiménez, F.J.; Molina, J.A.; Aguilar, M.V.; Meseguer, I.; Mateos-Vega, C.J.; González-Muñoz, M.J.; de Bustos, F.; Martínez-Salio, A.; Ortí-Pareja, M.; Zurdo, M.; et al. Cerebrospinal fluid levels of transition metals in patients with Parkinson’s disease. J. Neural Transm. 1998, 105, 497–505.
  6. Kocatürk, P.; Akbostanci, M.; Tan, F.; Kavas, G. Superoxide dismutase activity and zinc and copper concentrations in Parkinson’s disease. Pathophysiology 2000, 7, 63–67.
  7. Molina, J.A.; Jiménez-Jiménez, F.J.; Aguilar, M.V.; Meseguer, I.; Mateos-Vega, C.J.; González-Muñoz, M.J.; de Bustos, F.; Porta, J.; Ortí-Pareja, M.; Zurdo, M.; et al. Cerebrospinal fluid levels of transition metals in patients with Alzheimer’s disease. J. Neural Transm. 1998, 105, 479–488.
  8. Zhao, H.W.; Lin, J.; Wang, X.B.; Cheng, X.; Wang, J.Y.; Hu, B.L.; Zhang, Y.; Zhang, X.; Zhu, J.H. Assessing plasma levels of selenium, copper, iron and zinc in patients of Parkinson’s disease. PLoS ONE 2013, 8, 1–10.
  9. Alimonti, A.; Bocca, B.; Pino, A.; Ruggieri, F.; Forte, G.; Sancesario, G. Elemental profile of cerebrospinal fluid in patients with Parkinson’s disease. J. Trace Elem. Med. Biol. 2007, 21, 234–241.
  10. Ayton, S.; Finkelstein, D.; Cherny, R.; Bush, A.; Adlard, P. Zinc in Alzheimer’s and Parkinson’s Diseases. In Encyclopedia of Metalloproteins; Springer New York: New York, NY, USA, 2013; pp. 2433–2441. ISBN 9781461415336.
  11. Forte, G.; Bocca, B.; Senofonte, O.; Petrucci, F.; Brusa, L.; Stanzione, P.; Zannino, S.; Violante, N.; Alimonti, A.; Sancesario, G. Trace and major elements in whole blood, serum, cerebrospinal fluid and urine of patients with Parkinson’s disease. J. Neural Transm. 2004, 111, 1031–1040.
  12. Fukushima, T.; Tan, X.; Luo, Y.; Kanda, H. Serum vitamins and heavy metals in blood and urine, and the correlations among them in parkinson’s disease patients in China. Neuroepidemiology 2011, 36, 240–244.
  13. Gellein, K.; Syversen, T.; Steinnes, E.; Nilsen, T.; Dahl, O.; Mitrovic, S.; Duraj, D.; Flaten, T. Trace elements in serum from patients with Parkinson’s disease-a prospective case-control study. The Nord-Trøndelag Health Study (HUNT). Brain Res. 2008, 1219, 111–115.
  14. Hozumi, I.; Hasegawa, T.; Honda, A.; Ozawa, K.; Hayashi, Y.; Hashimoto, K.; Yamada, M.; Koumura, A.; Sakurai, T.; Kimura, A.; et al. Patterns of levels of biological metals in CSF differ among neurodegenerative diseases. J. Neurol. Sci. 2011, 303, 95–99.
  15. Squitti, R.; Gorgone, G.; Panetta, V.; Lucchini, R.; Bucossi, S.; Albini, E.; Alessio, L.; Alberici, A.; Melgari, J.; Benussi, L.; et al. Implications of metal exposure and liver function in Parkinsonian patients resident in the vicinities of ferroalloy plants. J. Neural Transm. 2009, 116, 1281–1287.
  16. Adani, G.; Filippini, T.; Michalke, B.; Vinceti, M. Selenium and Other Trace Elements in the Etiology of Parkinson’s Disease: A Systematic Review and Meta-Analysis of Case-Control Studies. Neuroepidemiology 2020, 54, 1–23.
  17. Du, K.; Liu, M.; Zhong, X.; Wei, M. Decreased circulating Zinc levels in Parkinson’s disease: A meta-analysis study. Sci. Rep. 2017, 7, 1–8.
  18. Miyake, Y.; Tanaka, K.; Fukushima, W.; Sasaki, S.; Kiyohara, C.; Tsuboi, Y.; Yamada, T.; Oeda, T.; Miki, T.; Kawamura, N.; et al. Dietary intake of metals and risk of Parkinson’s disease: A case-control study in Japan. J. Neurol. Sci. 2011, 306, 98–102.
  19. Cheng, P.; Yu, J.; Huang, W.; Bai, S.; Zhu, X.; Qi, Z.; Shao, W.; Xie, P. Dietary intake of iron, zinc, copper, and risk of Parkinson’s disease: A meta-analysis. Neurol. Sci. 2015, 36, 2269–2275.
  20. Powers, K.; Smith-Weller, T.; Franklin, G.; Longstreth, W.; Swanson, P.; Checkoway, H. Parkinson’s disease risks associated with dietary iron, manganese, and other nutrient intakes. Neurology 2003, 60, 1761–1766.
  21. Marreiro, D.; Cruz, K.; Morais, J.; Beserra, J.; Severo, J.; Soares de Oliveira, A. Zinc and oxidative stress: Current mechanisms. Antioxidants 2017, 6, 24.
  22. Méndez-Álvarez, E.; Soto-Otero, R.; Hermida-Ameijeiras, Á.; López-Real, A.; Labandeira-García, J. Effects of aluminum and zinc on the oxidative stress caused by 6-hydroxydopamine autoxidation: Relevance for the pathogenesis of Parkinson’s disease. Biochim. Biophys. Acta Mol. Basis Dis. 2002, 1586, 155–168.
  23. Ajjimaporn, A.; Shavali, S.; Ebadi, M.; Govitrapong, P. Zinc rescues dopaminergic SK–N–SH cell lines from methamphetamine-induced toxicity. Brain Res. Bull. 2008, 77, 361–366.
  24. Ajjimaporn, A.; Swinscoe, J.; Shavali, S.; Govitrapong, P.; Ebadi, M. Metallothionein provides zinc-mediated protective effects against methamphetamine toxicity in SK-N-SH cells. Brain Res. Bull. 2005, 67, 466–475.
  25. Ajjimaporn, A.; Phansuwan-Pujito, P.; Ebadi, M.; Govitrapong, P. Zinc protects SK-N-SH cells from methamphetamine-induced α-synuclein expression. Neurosci. Lett. 2007, 419, 59–63.
  26. Hristova, V.; Beasley, S.; Rylett, R.; Shaw, G. Identification of a novel Zn 2+ -binding domain in the autosomal recessive juvenile Parkinson-related E3 ligase parkin. J. Biol. Chem. 2009, 284, 14978–14986.
  27. Saini, N.; Schaffner, W. Zinc supplement greatly improves the condition of parkin mutant Drosophila. Biol. Chem. 2010, 391, 513–518.
  28. Pals, P.; Van Everbroeck, B.; Grubben, B.; Viaene, M.; Dom, R.; Van Der Linden, C.; Santens, P.; Martin, J.; Cras, P. Case-control study of environmental risk factors for Parkinson’s disease in Belgium. Eur. J. Epidemiol. 2003, 18, 1133–1142.
  29. Dexter, D.; Carayon, A.; Javoy-agid, F.; Agid, Y.; Wells, F.; Daniel, S.; Lees, A.; Jenner, P.; Marsden, C. Alterations in the levels of iron, ferritin and other trace metals in parkinson’s disease and other neurodegenerative diseases affecting the basal ganglia. Brain 1991, 114, 1953–1975.
  30. Dexter, D.; Wells, F.; Lee, A.; Agid, F.; Agid, Y.; Jenner, P.; Marsden, C. Increased Nigral Iron Content and Alterations in Other Metal Ions Occurring in Brain in Parkinson’s Disease. J. Neurochem. 1989, 52, 1830–1836.
  31. Genoud, S.; Roberts, B.; Gunn, A.; Halliday, G.; Lewis, S.; Ball, H.; Hare, D.; Double, K. Subcellular compartmentalisation of copper, iron, manganese, and zinc in the Parkinson’s disease brain. Metallomics 2017, 9, 1447–1455.
  32. Hirsch, E.; Brandel, J.; Galle, P.; Javoy-Agid, F.; Agid, Y. Iron and Aluminum Increase in the Substantia Nigra of Patients with Parkinson’s Disease: An X-Ray Microanalysis. J. Neurochem. 1991, 56, 446–451.
  33. Kumar, A.; Singh, B.; Ahmad, I.; Shukla, S.; Patel, D.; Srivastava, G.; Kumar, V.; Pandey, H.; Singh, C. Involvement of NADPH oxidase and glutathione in zinc-induced dopaminergic neurodegeneration in rats: Similarity with paraquat neurotoxicity. Brain Res. 2012, 1438, 48–64.
  34. Kumar, V.; Singh, D.; Singh, B.; Singh, S.; Mittra, N.; Jha, R.; Patel, D.; Singh, C. Alpha-synuclein aggregation, Ubiquitin proteasome system impairment, and l-Dopa response in zinc-induced Parkinsonism: Resemblance to sporadic Parkinson’s disease. Mol. Cell. Biochem. 2017, 444, 149–160.
  35. Lee, J.; Son, H.; Choi, J.; Cho, E.; Kim, J.; Chung, S.; Hwang, O.; Koh, J. Cytosolic labile zinc accumulation in degenerating dopaminergic neurons of mouse brain after MPTP treatment. Brain Res. 2009, 1286, 208–214.
  36. Tamano, H.; Morioka, H.; Nishio, R.; Takeuchi, A.; Takeda, A. AMPA-induced extracellular Zn2+ influx into nigral dopaminergic neurons causes movement disorder in rats. Neurotoxicology 2018, 69, 23–28.
  37. Tamano, H.; Morioka, H.; Nishio, R.; Takeuchi, A.; Takeda, A. Blockade of Rapid Influx of Extracellular Zn2+ into Nigral Dopaminergic Neurons Overcomes Paraquat-Induced Parkinson’s Disease in Rats. Mol. Neurobiol. 2018, 56, 4539–4548.
  38. Tamano, H.; Nishio, R.; Morioka, H.; Takeda, A. Extracellular Zn 2+ Influx into Nigral Dopaminergic Neurons Plays a Key Role for Pathogenesis of 6-Hydroxydopamine-Induced Parkinson’s Disease in Rats. Mol. Neurobiol. 2018, 56, 435–443.
  39. Tarohda, T.; Ishida, Y.; Kawai, K.; Yamamoto, M.; Amano, R. Regional distributions of manganese, iron, copper, and zinc in the brains of 6-hydroxydopamine-induced parkinsonian rats. Anal. Bioanal. Chem. 2005, 383, 224–234.
  40. Escames, G.; Acuña-Castrovlejo, D.; León, J.; Vives, F. Melatonin interaction with magnesium and zinc in the response of the striatum to sensorimotor cortical stimulation in the rat. J. Pineal Res. 1998, 24, 123–129.
  41. Granzotto, A.; Sensi, S. Intracellular zinc is a critical intermediate in the excitotoxic cascade. Neurobiol. Dis. 2015, 81, 25–37.
  42. Hussain, S.; Ali, S. Zinc potentiates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced dopamine depletion in caudate nucleus of mice brain. Neurosci. Lett. 2002, 335, 25–28.
  43. Tsunemi, T.; Krainc, D. Zn2+ dyshomeostasis caused by loss of ATP13A2/PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulation. Hum. Mol. Genet. 2014, 23, 2791–2801.
  44. Kong, S.; Chan, B.; Park, J.; Hill, K.; Aitken, J.; Cottle, L.; Farghaian, H.; Cole, A.; Lay, P.; Sue, C.; et al. Parkinson’s disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes α-Synuclein externalization via exosomes. Hum. Mol. Genet. 2014, 23, 2816–2833.
  45. Park, J.S.; Koentjoro, B.; Veivers, D.; Mackay-Sim, A.; Sue, C.M. Parkinson’s disease-associated human ATP13A2 (PARK9) deficiency causes zinc dyshomeostasis and mitochondrial dysfunction. Hum. Mol. Genet. 2014, 23, 2802–2815.
  46. Lin, A.M.Y.; Fan, S.F.; Yang, D.M.; Hsu, L.L.; Yang, C.H.J. Zinc-induced apoptosis in substantia nigra of rat brain: Neuroprotection by vitamin D3. Free Radic. Biol. Med. 2003, 34, 1416–1425.
  47. Lin, A. Coexistence of zinc and iron augmented oxidative injuries in the nigrostriatal dopaminergic system of SD rats. Free Radic. Biol. Med. 2001, 30, 225–231.
  48. Kumar, A.; Ahmad, I.; Shukla, S.; Singh, B.; Patel, D.; Pandey, H.; Singh, C. Effect of zinc and paraquat co-exposure on neurodegeneration: Modulation of oxidative stress and expression of metallothioneins, toxicant responsive and transporter genes in rats. Free Radic. Res. 2010, 44, 950–965.
  49. Blomeley, C.; Bracci, E. Substance P depolarizes striatal projection neurons and facilitates their glutamatergic inputs. J. Physiol. 2008, 586, 2143–2155.
  50. Jiang, Q.; Li, M.; Papasian, C.; Branigan, D.; Xiong, Z.; Wang, J.; Chu, X. Characterization of acid-sensing ion channels in medium spiny neurons of mouse striatum. Neuroscience 2009, 162, 55–66.
  51. Galindo, M.; Solesio, M.; Atienzar-Aroca, S.; Zamora, M.; Jordán Bueso, J. Mitochondrial dynamics and mitophagy in the 6-Hydroxydopamine preclinical model of Parkinson’s disease. Parkinsons Dis. 2012, 2012.
  52. Chauhan, A.; Mittra, N.; Kumar, V.; Patel, D.; Singh, C. Inflammation and B-cell Lymphoma-2 Associated X Protein Regulate Zinc-Induced Apoptotic Degeneration of Rat Nigrostriatal Dopaminergic Neurons. Mol. Neurobiol. 2016, 53, 5782–5795.
  53. Kumar, V.; Singh, B.; Chauhan, A.; Singh, D.; Patel, D.; Singh, C. Minocycline Rescues from Zinc-Induced Nigrostriatal Dopaminergic Neurodegeneration: Biochemical and Molecular Interventions. Mol. Neurobiol. 2016, 53, 2761–2777.
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