PHARMASPIRE - Volume 11, Issue 4, October - December, 2019

Pages: 97-106
Print Article   Download XML  Download PDF

Novel targets for mitochondria dysfunction and oxidative stress in Parkinson’s disease

Author: Karamjeet Kaur, Taranjit Singh, Dilpreet Kaur, Sania Grover, Shamsher Singh

Category: Pharmaceutics

Abstract:

Parkinson is a progressive neurological disorder affecting neurons of basal ganglia. It generally consists of slowing down in initiation and execution of muscle movements generally characterized by tremors, muscle rigidity, bradykinesia, and gait abnormalities. Most of the cases of Parkinson’s disease are idiopathic, but it is likely a result of interaction among aging, genetic factors, and environmental factors. The genes responsible for Parkinson can be alpha-synuclein (SNCA), PTEN-induced kinase 1, PARK8, etc. Autosomal dominant forms of Parkinson are associated with mutation of α-syn (PARK 1&4) and Leucine-rich repeat kinase 2. The most important factor in pathophysiology can be free radicals and mitochondrial dysfunction which is induced by mutation and deposition of SNCA protein. An increase in the levels of glutamate may also lead to the overproduction of free radicals and reactive oxygen species. Several antioxidants, such as glutathione (GSH), are present in substantia nigra pars compacta region of basal ganglia to limit the damage by free radicals. In the premotor stage of idiopathic Parkinson’s disease, Lewy bodies are initially found in the medulla oblongata and some other regions. As the disease progress, Lewy bodies ascend to the midbrain, especially SNpc. The spread of Lewy body to cortex occurs in the advanced stage. The clinically detectable stage idiopathic Parkinson’s disease is generally after 70–80% damage of the SNC neurons. The available therapies provide symptomatic benefits and choice of therapy is patient specific. The choice of therapy is much critical for optimizing short- and long-term outcomes.

Keywords: Parkinson’s disease, mitochondrial dysfunction, oxidative stress, alpha-synuclein, Lewy bodies, substantia nigra pars compacta

References:

1. Bezard E, Gross CE, Brotchie JM. Presymptomatic compensation in Parkinson’s disease is not dopamine-mediated. Trends Neurosci 2003;26:215-21.

2. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. Parkinson disease. Nat Rev Dis Primers 2017;3:1-21.

3. Marchi S, Patergnani S, Missiroli S, Morciano G, Rimessi A, Wieckowski MR, et al. Mitochondrial and endoplasmic reticulum calcium homeostasis and cell death. Cell Calcium 2018;69:62-72.

4. Roy A, Ganguly A, Dasgupta SB, Das BB, Pal C, Jaisankar P, et al. Mitochondriadependent reactive oxygen species-mediated programmed cell death induced by 3, 3’-diindolylmethane through inhibition of F0F1-ATP synthase in unicellular protozoan parasite Leishmania donovani. Mol Pharmacol 2008;74:1292-307.

5. Lu J, Sharma LK, Bai Y. Implications of mitochondrial DNA mutations and mitochondrial dysfunction in tumorigenesis. Cell Res 2009;19:802-15.

6. Gerlach M, Riederer P, Przuntek H, Youdim MB. MPTP mechanisms of neurotoxicity and their implications for Parkinson’s disease. Eur J Pharmacol 1991;208:273-86.

7. Liu Y, Fiskum G, Schubert D. Generation of reactive oxygen species by the mitochondrial electron transport chain. J Neurochem 2002;80:780-7.

8. Nakka VP, Gusain A, Mehta SL, Raghubir R. Molecular mechanisms of apoptosis in cerebral ischemia: Multiple neuroprotective opportunities. Mol Neurobiol 2008;37:7-38.

9. Ryan BJ, Hoek S, Fon EA, Wade-Martins R. Mitochondrial dysfunction and mitophagy in Parkinson’s: From familial to sporadic disease. Trends Biochem Sci 2015;40:200-10.

10. Lin MT, Simon DK, Ahn CH, Kim LM, Beal MF. High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer’s disease brain. Hum Mol Genet 2002;11:133-45.

11. Ekstrand MI, Terzioglu M, Galter D, Zhu S, Hofstetter C, Lindqvist E, et al. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc Natl Acad Sci 2007;104:1325-30.

12. Banerjee R, Starkov AA, Beal MF, Thomas B. Mitochondrial dysfunction in the limelight of Parkinson’s disease pathogenesis. Biochim Biophys Acta Mol Basis Dis 2009;1792:651-63.

13. Plun-Favreau H, Klupsch K, Moisoi N, Gandhi S, Kjaer S, Frith D, et al. The mitochondrial protease HtrA2 is regulated by Parkinson’s disease-associated kinase PINK1. Nat Cell Biol 2007;9:1243-52.

14. Emamzadeh FN. Alpha-synuclein structure, functions, and interactions. J Res Med Sci 2016;21:29.

15. Coulom H, Birman S. Chronic exposure to rotenone models sporadic Parkinson’s disease in Drosophila melanogaster. J Neurosci 2004;24:10993-8.

16. Choubey V, Safiulina D, Vaarmann A, Cagalinec M, Wareski P, Kuum M, et al. Mutant A53T α-synuclein induces neuronal death by increasing mitochondrial autophagy. J Biol Chem 2011;286:10814-24.

17. Cole NB, DiEuliis D, Leo P, Mitchell DC, Nussbaum RL. Mitochondrial translocation of α-synuclein is promoted by intracellular acidification. Exp Cell Res 2008;314:2076-89.

18. Parihar MS, Parihar A, Fujita M, Hashimoto M, Ghafourifar P. Mitochondrial association of alpha-synuclein causes oxidative stress. Cell Mol Life Sci 2008;65:1272-84.

19. Sampaio-Marques B, Felgueiras C, Silva A, Rodrigues M, Tenreiro S, FranssensV, et al. SNCA (α-synuclein)-induced toxicity in yeast cells is dependent on Sir2- mediated mitophagy. Autophagy 2012;8:1494-509.

20. Kaul SC, Deocaris CC, Wadhwa R. Three faces of mortalin: A housekeeper, guardian and killer. Exp Gerontol 2007;42:263-74.

21. Bosch M, Marí M, Herms A, Fernández A, Fajardo A, Kassan A, et al. Caveolin-1 deficiency causes cholesterol-dependent mitochondrial dysfunction and apoptotic susceptibility. Curr Biol 2011;21:681-6.

22. Nakamura K, Nemani VM, Azarbal F, Skibinski G, Levy JM, Egami K, et al. Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein α-synuclein. J Biol Chem 2011;286:20710-26.

23. Ebrahimi-Fakhari D, Cantuti-Castelvetri I, Fan Z, Rockenstein E, Masliah E, Hyman BT, et al. Distinct roles in vivo for the ubiquitin-proteasome system and the autophagy-lysosomal pathway in the degradation of α-synuclein. J Neurosci 2011;31:14508-20.

24. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D. Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy. Science 2004;305:1292-5.

25. Zhang J. Autophagy and mitophagy in cellular damage control. Redox Biol 2013;1:19-23.

26. Wang B, Abraham N, Gao G, Yang Q. Dysregulation of autophagy and mitochondrial function in Parkinson’s disease. Transl Neurodegener 2016;5:19.

27. Guo L, Wang W, Chen SG. Leucine-rich repeat kinase 2: Relevance to Parkinson’s disease. Int J Biochem Cell Biol 2006;38:1469-75.

28. Paisan-Ruiz C, Lewis PA, Singleton AB. LRRK2: Cause, risk, and mechanism. J Parkinson’s Dis 2013;3:85-103.

29. Dev KK. PDZ domain protein-protein interactions: A case study with PICK1. Curr Top Med Chem 2007;7:3-20.

30. Ramonet D, Daher JP, Lin BM, Stafa K, Kim J, Banerjee R, et al. Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS One 2011;6:e18568.

31. Winklhofer KF, Haass C. Mitochondrial dysfunction in Parkinson’s disease. Biochim Biophys Acta Mol Basis Dis 2010;1802:29-44.

32. Li JQ, Tan L, Yu JT. The role of the LRRK2 gene in parkinsonism. Mol Neurodegener 2014;9:47.

33. Bossy-Wetzel E, Barsoum MJ, Godzik A, Schwarzenbacher R, Lipton SA. Mitochondrial fission in apoptosis, neurodegeneration and aging. Curr Opin Cell Biol 2003;15:706-16.

34. Bonda DV, Smith MV, Perry G, Lee HG, Wang X, Zhu X. The mitochondrial dynamics of Alzheimer’s disease and Parkinson’s disease offer important opportunities for therapeutic intervention. Curr Pharm Design 2011;17:3374-80.

35. Filichia E, Hoffer B, Qi X, Luo Y. Inhibition of Drp1 mitochondrial translocation provides neural protection in dopaminergic system in a Parkinson’s disease model induced by MPTP. Sci Rep 2016;6:1-3.

36. Dias V, Junn E, Mouradian MM. The role of oxidative stress in Parkinson’s disease. J Parkinson’s Dis 2013;3:461-91.

37. Gaki GS, Papavassiliou AG. Oxidative stress-induced signaling pathways implicated in the pathogenesis of Parkinson’s disease. Neuromol Med 2014;16:217-30.

38. Niu J, Yu M, Wang C, Xu Z. Leucine-rich repeat kinase 2 disturbs mitochondrial dynamics via dynamin-like protein. J Neurochem 2012;122:650-8.

39. Kaidery NA, Thomas B. Current perspective of mitochondrial biology in Parkinson’s disease. Neurochem Int 2018;117:91-113.

40. Wang X, Yan MH, Fujioka H, Liu J, Wilson-Delfosse A, Chen SG, et al. LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1. Hum Mol Genet 2012;21:1931-44.

41. Kang UB, Marto JA. Leucine-rich repeat kinase 2 and Parkinson’s disease. Proteomics 2017;17:1600092.

42. Von Coelln R, Dawson VL, Dawson TM. Parkin-associated Parkinson’s disease. Cell Tissue Res 2004;318:175-84.

43. Joch M, Ase AR, Chen CX, MacDonald PA, Kontogiannea M, Corera AT, et al. Parkin-mediated monoubiquitination of the PDZ protein PICK1 regulates the activity of acid-sensing ion channels. Mol Biol Cell 2007;18:3105-18.

44. Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM. Parkin functions as an E2-dependent ubiquitin-protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc Natl Acad Sci 2000;97:13354-9.

45. Zhang D. Protein Kinase C-delta in Dopaminergic System and Experimental Models of Parkinson’s Disease. Iowa: Iowa State University; 2008.

46. Büeler H. Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson’s disease. Exp Neurol 2009;218:235-46.

47. LaVoie MJ, Ostaszewski BL, Weihofen A, Schlossmacher MG, Selkoe DJ. Dopamine covalently modifies and functionally inactivates parkin. Nat Med 2005;11:1214-21.

48. Abou-Sleiman PM, Muqit MM, Wood NW. Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nat Rev Neurosci 2006;7:207-19.

49. Exner N, Lutz AK, Haass C, Winklhofer KF. Mitochondrial dysfunction in Parkinson’s disease: Molecular mechanisms and pathophysiological consequences. EMBO J 2012;31:3038-62.

50. Takatori S, Ito G, Iwatsubo T. Cytoplasmic localization and proteasomal degradation of N-terminally cleaved form of PINK1. Neurosci Lett 2008;430:13-7.

51. Wirawan E, Berghe TV, Lippens S, Agostinis P, Vandenabeele P. Autophagy: For better or for worse. Cell Res 2012;22:43-61.

52. Gautier CA, Kitada T, Shen J. Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc Natl Acad Sci 2008;105:11364-9.

53. Marongiu R, Spencer B, Crews L, Adame A, Patrick C, Trejo M, et al. Mutant pink1 induces mitochondrial dysfunction in a neuronal cell model of Parkinson’s disease by disturbing calcium flux. J Neurochem 2009;108:1561-74.

54. Deas E, Wood NW, Plun-Favreau H. Mitophagy and Parkinson’s disease: The PINK1-parkin link. Biochim Biophys Acta Mol Cell Res 2011;1813:623-33.

55. Matsuda N. Phospho-ubiquitin: Upending the PINK-parkin-ubiquitin cascade. J Biochem 2016;159:379-85.

56. Narendra DP. Parkin/pink1 pathway for the selective isolation and degradation of impaired mitochondria. In: Mitochondrial Mechanisms of Degeneration and Repair in Parkinson’s Disease. Cham: Springer; 2016. p. 159-82.

57. Martinat C, Shendelman S, Jonason A, Leete T, Beal MF, Yang L, et al. Sensitivity to oxidative stress in DJ-1-deficient dopamine neurons: An ES-derived cell model of primary parkinsonism. PLoS Biol 2004;2:e327.

58. Chan JY, Chan SH. Activation of endogenous antioxidants as a common therapeutic strategy against cancer, neurodegeneration and cardiovascular diseases: A lesson learnt from DJ-1. Pharmacol Ther 2015;156:69-74.

59. Kim RH, Smith PD, Aleyasin H, Hayley S, Mount MP, Pownall S, et al. Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyrindine (MPTP) and oxidative stress. Proc Natl Acad Sci 2005;102:5215-20.

60. Labbe G, Pessayre D, Fromenty B. Drug-induced liver injury through mitochondrial dysfunction: Mechanisms and detection during preclinical safety studies. Fundam Clin Pharmacol 2008;22:335-53.

61. Morissette M, Litim N, Di Paolo T. Natural phytoestrogens: A class of promising neuroprotective agents for Parkinson disease. In: Discovery and Development of Neuroprotective Agents from Natural Products. Netherlands: Elsevier; 2018. p. 9-61.

62. Mukherjee UA, Ong SB, Ong SG, Hausenloy DJ. Parkinson’s disease proteins: Novel mitochondrial targets for cardio protection. Pharmacol Ther 2015;156:34-43.

63. Letts JA, Fiedorczuk K, Sazanov LA. The architecture of respiratory super complexes. Nature 2016;537:644-8.

64. Xiong N, Long X, Xiong J, Jia M, Chen C, Huang J, et al. Mitochondrial complex I inhibitor rotenone-induced toxicity and its potential mechanisms in Parkinson’s disease models. Crit Rev Toxicol 2012;42:613-32.

65. Bové J, Perier C. Neurotoxin-based models of Parkinson’s disease. Neuroscience 2012;211:51-76.

66. Karunakaran S, Diwakar L, Saeed U, Agarwal V, Ramakrishnan S, Iyengar S, et al. Activation of apoptosis signal regulating kinase 1 (ASK1) and translocation of death-associated protein, Daxx, in substantia nigra pars compacta in a mouse model of Parkinson’s disease: Protection by α-lipoic acid. FASEB J 2007;21:2226-36.

67. Im JY, Lee KW, Junn E, Mouradian MM. DJ-1 protects against oxidative damage by regulating the thioredoxin/ASK1 complex. Neurosci Res 2010;67:203-8.

68. Waak J, Weber SS, Görner K, Schall C, Ichijo H, Stehle T, et al. Oxidizable residues mediating protein stability and cytoprotective interaction of DJ-1 with apoptosis signal-regulating kinase 1. J Biol Chem 2009;284:14245-57.

69. Gao H, Yang W, Qi Z, Lu L, Duan C, Zhao C, et al. DJ-1 protects dopaminergic neurons against rotenone-induced apoptosis by enhancing ERK-dependent mitophagy. J Mol Biol 2012;423:232-48.

70. Henchcliffe C, Beal MF. Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat Clin Pract Neurol 2008;4:600-9.

71. Kuwana T, Newmeyer DD. Bcl-2-family proteins and the role of mitochondria in apoptosis. Curr Opin Cell Biol 2003;15:691-9.

72. Koh H, Kim H, Kim MJ, Park J, Lee HJ, Chung J. Silent information regulator 2 (Sir2) and forkhead box O (FOXO) complement mitochondrial dysfunction and dopaminergic neuron loss in Drosophila PTEN-induced kinase 1 (PINK1) null mutant. J Biol Chem 2012;287:12750-8.

73. Ma X, Kalakonda S, Srinivasula SM, Reddy SP, Platanias LC, Kalvakolanu DV. GRIM-19 associates with the serine protease HtrA2 for promoting cell death. Oncogene 2007;26:4842-9.

74. Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nat Rev Genet 2005;6:389-402.

75. Tuppen HA, Blakely EL, Turnbull DM, Taylor RW. Mitochondrial DNA mutations and human disease. Biochim Biophys Acta Bioenerget 2010;1797:113-28.

76. Bahr T, Welburn K, Donnelly J, Bai Y. Emerging model systems and treatment approaches for Leber’s hereditary optic neuropathy: Challenges and opportunities. Biochim Biophys Acta Mol Basis Dis 2020;24:165743.

77. Bohr VA, Stevnsner T, de Souza-Pinto NC. Mitochondrial DNA repair of oxidative damage in mammalian cells. Gene 2002;286:127-34.

78. Fariss MW, Zhang JG. Vitamin E therapy in Parkinson’s disease. Toxicology 2003;189:129-46.

79. Fujita KA, Ostaszewski M, Matsuoka Y, Ghosh S, Glaab E, Trefois C, et al. Integrating pathways of Parkinson’s disease in a molecular interaction map. Mol Neurobiol 2014;49:88-102.

80. Chu Y, Kordower JH. Age-associated increases of α-synuclein in monkeys and humans are associated with nigrostriatal dopamine depletion: Is this the target for Parkinson’s disease? Neurobiol Dis 2007;25:134-49.

81. Lim GG, Zhang C, Lim KL. Role of autophagy in Parkinson’s disease. In: Autophagy-a double-edged sword: Cell Survival or Death? Vol. 17. London: IntechOpen; 2013. p. 353.

82. Gatt AP, Jones EL, Francis PT, Ballard C, Bateman JM. Association of a polymorphism in mitochondrial transcription factor A (TFAM) with Parkinson’s disease dementia but not dementia with Lewy bodies. Neurosci Lett 2013;557:177-80.

83. Gaweda-Walerych K, Safranow K, Maruszak A, Bialecka M, KlodowskaDuda G, Czyzewski K, et al. Mitochondrial transcription factor A variants and the risk of Parkinson’s disease. Neurosci Lett 2010;469:24-9.

84. Federico A, Cardaioli E, Da Pozzo P, Formichi P, Gallus GN, Radi E. Mitochondria, oxidative stress and neurodegeneration. J Neurol Sci 2012;322:254-62.

85. Tzoulis C, Bindoff LA. Acute mitochondrial encephalopathy reflects neuronal energy failure irrespective of which genome the genetic defect affects. Brain 2012;135:3627-34.

86. Valko M, Rhodes C, Moncol J, Izakovic MM, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 2006;160:1-40.

87. Lambert AJ, Brand MD. Reactive oxygen species production by mitochondria. In: Mitochondrial DNA. United States: Humana Press; 2009. p. 165-81.

88. Bergamini CM, Gambetti S, Dondi A, Cervellati C. Oxygen, reactive oxygen species and tissue damage. Curr Pharm Design 2004;10:1611-26. 89. Radak Z, Zhao Z, Goto S, Koltai E. Age-associated neurodegeneration and oxidative damage to lipids, proteins and DNA. Mol Aspects Med 2011;32:305-15. 90. Hayashi M. Oxidative stress in developmental brain disorders. Neuropathology 2009;29:1-8.

91. Boukhenouna S, Wilson MA, Bahmed K, Kosmider B. Reactive oxygen species in chronic obstructive pulmonary disease. Oxid Med Cell Longev 2018;2018:5730395.

92. Ferroni P, Barbanti P, Della-Morte D, Palmirotta R, Jirillo E, Guadagni F. Redox mechanisms in migraine: Novel therapeutics and dietary interventions. Antioxid Redox Signal 2018;28:1144-83.

93. Gmitterova K, Heinemann U, Gawinecka J, Varges D, Ciesielczyk B, Valkovic P, et al. 8-OHdG in cerebrospinal fluid as a marker of oxidative stress in various neurodegenerative diseases. Neurodegener Dis 2009;6:263-9.

94. Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR. Oxidative stress and Parkinson’s disease. Front Neuroanat 2015;9:91.

95. Miyazaki I, Asanuma M. Dopaminergic neuron-specific oxidative stress caused by dopamine itself. Acta Med Okayama 2008;62:141-50.

96. Choi SJ, Panhelainen A, Schmitz Y, Larsen KE, Kanter E, Wu M, et al. Changes in neuronal dopamine homeostasis following 1-methyl-4-phenylpyridinium (MPP+) exposure. J Biol Chem 2015;290:6799-809.

97. Arshad AR, Sulaiman SA, Saperi AA, Jamal R, Ibrahim NM, Murad NA. MicroRNAs and target genes as biomarkers for the diagnosis of early onset of Parkinson disease. Front Mol Neurosci 2017;10:352.

98. Vallone D, Picetti R, Borrelli E. Structure and function of dopamine receptors. Neurosci Biobehav Rev 2000;24:125-32.

99. Maruszak A, ?ekanowski C. Mitochondrial dysfunction and Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry 2011;35:320-30.

100. Dev KK, Hofele K, Barbieri S, Buchman VL, van der Putten H. Part II: α-synuclein and its molecular pathophysiological role in neurodegenerative disease. Neuropharmacology 2003;45:14-44.

101. Hwang O. Role of oxidative stress in Parkinson’s disease. Exp Neurobiol 2013;22:11-7.

102. Freeman D, Cedillos R, Choyke S, Lukic Z, McGuire K, Marvin S, et al. Alphasynuclein induces lysosomal rupture and cathepsin dependent reactive oxygen species following endocytosis. PLoS One 2013;8:e62143.

103. Dickson DW, Braak H, Duda JE, Duyckaerts C, Gasser T, Halliday GM, et al. Neuropathological assessment of Parkinson’s disease: Refining the diagnostic criteria. Lancet Neurol 2009;8:1150-7.

104. Tohgi H, Abe T, Saheki M, Hamato F, Sasaki K, Takahashi S. Reduced and oxidized forms of glutathione and α-tocopherol in the cerebrospinal fluid of parkinsonian patients: Comparison between before and after L-dopa treatment. Neurosci Lett 1995;184:21-4.

105. Smith AC, Boyd MR. Preferential effects of 1, 3-bis (2-chloroethyl)-1- nitrosourea (BCNU) on pulmonary glutathione reductase and glutathione/ glutathione disulfide ratios: Possible implications for lung toxicity. J Pharmacol Exp Ther 1984;229:658-63.

106. Dalle-Donne I, Rossi R, Colombo G, Giustarini D, Milzani A. Protein S-glutathionylation: A regulatory device from Bacteria to humans. Trends Biochem Sci 2009;34:85-96.

107. Gallogly MM, Mieyal JJ. Mechanisms of reversible protein glutathionylation in redox signaling and oxidative stress. Curr Opin Pharmacol 2007;7:381-91

. 108. Reitman ZJ, Yan H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: Alterations at a crossroads of cellular metabolism. J Natl Cancer Inst 2010;102:932-41.

109. Yin F, Sancheti H, Cadenas E. Mitochondrial thiols in the regulation of cell death pathways. Antioxid Redox Signal 2012;17:1714-27.

110. Kang JF, Tang BS, Guo JF. The progress of induced pluripotent stem cells as models of Parkinson’s disease. Stem Cells Int 2016;2016:4126214. 111. Luo Y, Hoffer A, Hoffer B, Qi X. Mitochondria: A therapeutic target for Parkinson’s disease? Int J Mol Sci 2015;16:20704-30.

112. Atashrazm F, Dzamko N. LRRK2 inhibitors and their potential in the treatment of Parkinson’s disease: Current perspectives. Clin Pharmacol 2016;8:177.

113. Shiba-Fukushima K, Imai Y, Yoshida S, Ishihama Y, Kanao T, Sato S, et al. PINK1-mediated phosphorylation of the Parkin ubiquitin-like domain primes mitochondrial translocation of Parkin and regulates mitophagy. Sci Rep 2012;2:1002.

114. Rosales-Corral S, Reiter RJ, Tan DX, Ortiz GG, Lopez-Armas G. Functional aspects of redox control during neuroinflammation. Antiox Redox Signal 2010;13:193-247.

115. McCoy MK, Cookson MR. DJ-1 regulation of mitochondrial function and autophagy through oxidative stress. Autophagy 2011;7:531-2.

116. Fernandez-Moriano C, González-Burgos E, Gómez-Serranillos MP. Mitochondria-targeted protective compounds in Parkinson’s and Alzheimer’s diseases. Oxid Med Cell Longev 2015;2015:30. 117. Gillies LA, Kuwana T. Apoptosis regulation at the mitochondrial outer membrane. J Cell Biochem 2014;115:632-40.

118. Qi X, Qvit N, Su YC, Mochly-Rosen D. A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity. J Cell Sci 2013;126:789-802.

119. Cheng A, Wan R, Yang JL, Kamimura N, Son TG, Ouyang X, et al. Involvement of PGC-1α in the formation and maintenance of neuronal dendritic spines. Nat Commun 2012;3:1-2.

120. Brown GC, Murphy MP, Jornayvaz FR, Shulman GI. Regulation of mitochondrial biogenesis. Essays Biochem 2010;47:69-84.

121. Johri A, Chandra A, Beal MF. PGC-1α, mitochondrial dysfunction, and Huntington’s disease. Free Radic Biol Med 2013;62:37-46.

122. Townsend DM, Tew KD, Tapiero H. The importance of glutathione in human disease. Biomed Pharmacother 2003;57:145-55.

123. 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;21:234-41.

124. Jenner P, Olanow CW. Understanding cell death in Parkinson’s disease. Ann Neurol 1998;44:S72-84.

125. Cacciatore I, Cornacchia C, Pinnen F, Mollica A, Di Stefano A. Prodrug approach for increasing cellular glutathione levels. Molecules 2010;15:1242-64.

126. Marchese A, Arciola CR, Coppo E, Barbieri R, Barreca D, Chebaibi S, et al. The natural plant compound carvacrol as an antimicrobial and anti-biofilm agent: Mechanisms, synergies and bio-inspired anti-infective materials. Biofouling 2018;34:630-56.

127. Chao J, Leung Y, Wang M, Chang RC. Nutraceuticals and their preventive or potential therapeutic value in Parkinson’s disease. Nutr Rev 2012;70:373-86.

128. Solla P, Cannas A, Marrosu F, Marrosu MG. Therapeutic interventions and adjustments in the management of Parkinson disease: Role of combined carbidopa/levodopa/entacapone (Stalevo®). Neuropsychiatr Dis Treat 2010;6:483.

129. Kerksick C, Willoughby D. The antioxidant role of glutathione and N-acetylcysteine supplements and exercise-induced oxidative stress. J Int Soc Sports Nutr 2005;2:38. 130.

Friedel HA, Goa KL, Benfield P. S-adenosyl-L-methionine. Drugs 1989;38:389- 416.

131. Packer L, Witt EH, Tritschler HJ. Alpha-lipoic acid as a biological antioxidant. Free Radic Biol Med 1995;19:227-50.

132. Decker EA. The role of phenolics, conjugated linoleic acid, carnosine, and pyrroloquinoline quinone as nonessential dietary antioxidants. Nutr Rev 1995;53:49-58.

133. Smeyne M, Smeyne RJ. Glutathione metabolism and Parkinson’s disease. Free Radic Biol Med 2013;62:13-25.

134. Maher P, Lewerenz J, Lozano C, Torres JL. A novel approach to enhancing cellular glutathione levels. J Neurochem 2008;107:690-700.