Advertisement

Molecular Marker and Therapeutic Regimen for Neurodegenerative Diseases

  • Sharmistha Dey
  • Nitish Rai
  • Shashank Shekhar
  • Amrendra Pratap Singh
  • Vertica Agnihotri
Chapter

Abstract

The aging brain and nervous system go through changes by natural processes over time. The gradual loss of nerve cells takes place in normal aging process, while in some cases, collapsed old nerve cells lead to lots of accumulation of nerve cell’s waste, eventually forming plaques and tangles. The plaques and tangles result in dementia (the memory loss) or movement disorder, which initiate different neurodegenerative diseases in aging. Disease-associated behavioral changes will start and become worse if it could not be detected in the early stage. It can be prevented by mental and physical exercise in normal aging process. Further, neurodegenerative disease in aging could be protected from promoting by early detection with potent molecular markers. The molecule which has direct or indirect role with the pathophysiology of the disease that reflects the insight for early diagnosis can distinguish disease accurately from normal. A molecular marker may simply refer to any biomolecule that can be estimated and utilized as a yardstick of a physiological or pathological state. In this chapter, the molecular markers have been described in context to the neuronal physiology and their potential diagnostic utility in neurodegeneration. This chapter presented the recently exploited biological molecules which have neuropathological role for the development of molecular markers in Alzheimer’s disease and Parkinson’s disease.

Keywords

Protein marker Neurodegeneration Alzheimer’s disease Parkinson’s disease Therapeutics 

References

  1. 1.
    Orgel LE (1963) The maintenance of the accuracy of protein synthesis and its relevance to ageing. Proc Natl Acad Sci USA 49:517–521PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Weissman A (1891) Essays upon heredity and kindred biological problems. Oxford University Press-Clarendon, OxfordGoogle Scholar
  4. 4.
    Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Dilman V (1954) Data regarding the origin of climacteric and the role of age-associated “perestroika” in the elevation of blood pressure, blood cholesterol levels, and body weight. Master’s Thesis, Leningrad.Google Scholar
  6. 6.
    Walford RL (1969) Immunologic aspects of aging. Klin Wochenschr 47:599–605PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Prince M, Wimo A, Guerchet M, Ali GC, Wu YT, Prina M (2015) The global impact of dementia: an analysis of prevalence, incidence, cost and trends. World Alzheimer Report Alzheimer’s Disease InternationalGoogle Scholar
  8. 8.
    Ritsner M (2009) The handbook of neuropsychiatric biomarkers, endophenotypes and genes. Springer, BerlinCrossRefGoogle Scholar
  9. 9.
    Prasher VP, Farrer MJ, Kessling AM, Fisher EM, West RJ, Barber PC, Butler AC (1998) Molecular mapping of Alzheimer-type dementia in Down’s syndrome. Ann Neurol 43:380–383PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Small SA, Duff K (2008) Linking Abeta and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis. Neuron 60:534–542PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Lee VM, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24:1121–1159PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Takashima A (2009) Amyloid-beta, tau, and dementia. J Alzheimers Dis 17:729–736PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Billingsley ML, Kincaid RL (1997) Regulated phosphorylation and dephosphorylation of tau protein: effects on microtubule interaction, intracellular trafficking and neurodegeneration. Biochem J 323:577–591PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Morris M, Maeda S, Vossel K, Mucke L (2011) The many faces of tau. Neuron 70:410–426PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Brunden KR, Trojanowski JQ, Lee VM (2009) Advances in tau-focused drug discovery for Alzheimer’s disease and related tauopathies. Nat Rev Drug Discov 8:783–793PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Blom ES, Giedraitis V, Zetterberg H, Fukumoto H, Blennow K, Hyman BT, Irizarry MC, Wahlund LO, Lannfelt L, Ingelsson M (2009) Rapid progression from mild cognitive impairment to Alzheimer’s disease in subjects with elevated levels of tau in cerebrospinal fluid and the APOE epsilon4/epsilon4 genotype. Dement Geriatr Cogn Disord 27:458–464PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Sämgård K, Zetterberg H, Blennow K, Hansson O, Minthon L, Londos E (2010) Cerebrospinal fluid total tau as a marker of Alzheimer’s disease intensity. Int J Geriatr Psychiatry 25:403–410PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Brickhouse M, O’Keefe K, Sullivan C, Rentz D, Marshall G, Dickerson B, Sperling R (2011) Hippocampal hyperactivation associated with cortical thinning in Alzheimer’s disease signature regions in nondemented elderly adults. J Neurosci 31:17680–17688PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Mucke L (2010) Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci 13:812–818PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Verret L, Mann EO, Hang GB, Barth AM, Cobos I, Ho K, Devidze N, Masliah E, Kreitzer AC, Mody I, Mucke L, Palop JJ (2012) Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell 149:708–721PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356CrossRefGoogle Scholar
  22. 22.
    Rachakonda V, Pan TH, LE WD (2004) Biomarkers of neurodegenerative disorders: how good are they? Cell Res 14:347–358PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Gowert NS, Donner L, Chatterjee M, Eisele YS, Towhid ST, Münzer P, Walker B, Ogorek I, Borst O, Grandoch M, Schaller M, Fischer JW, Gawaz M, Weggen S, Lang F, Jucker M, Elvers M (2014) Blood platelets in the progression of Alzheimer’s disease. PLoS One 9:e90523PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Padovani A, Borroni B, Colciaghi F, Pastorino L, Archetti S, Cottini E, Caimi L, Cattabeni F, Di Luca M (2001) Platelet amyloid precursor protein forms in AD: a peripheral diagnostic tool and a pharmacological target. Mech Ageing Dev 122:1997–2004PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Borroni B, Colciaghi F, Caltagirone C, Rozzini L, Broglio L, Cattabeni F, Di Luca M, Padovani A (2003) Platelet amyloid precursor protein abnormalities in mild cognitive impairment predict conversion to dementia of Alzheimer type: a 2-year follow-up study. Arch Neurol 60:1740–1744PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Luchsinger JA, Tang MX, Miller J, Green R, Mehta PD, Mayeux R (2007) Relation of plasma homocysteine to plasma amyloid beta levels. Neurochem Res 32:775–781PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Ruiz A, Pesini P, Espinosa A, Pérez-Grijalba V, Valero S, Sotolongo-Grau O, Alegret M, Monleón I, Lafuente A, Buendía M, Ibarria M, Ruiz S, Hernández I, San José I, Tárraga L, Boada M, Sarasa M (2013) Blood amyloid beta levels in healthy, mild cognitive impairment and Alzheimer’s disease individuals: replication of diastolic blood pressure correlations and analysis of critical covariates. PLoS One 8:e81334PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Sunderland T, Linker G, Mirza N, Putnam KT, Friedman DL, Kimmel LH, Bergeson J, Manetti GJ, Zimmermann M, Tang B, Bartko JJ, Cohen RM (2003) Decreased beta-amyloid 1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. JAMA 289:2094–2103PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Andreasen N, Sjogren M, Blennow K (2003) CSF markers for Alzheimer’s disease: total tau, phospho-tau and Aβ42. World J Biol Psychiatry 4:147–155PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Tapiola T, Alafuzoff I, Herukka SK, Parkkinen L, Hartikainen P, Soininen H, Pirttila T (2009) Cerebrospinal fluid β-amyloid 42 and tau proteins as biomarkers of Alzheimer type pathologic changes in the brain. Arch Neurol 66:382–389PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Zetterberg H, Wilson D, Andreasson U, Minthon L, Blennow K, Randall J, Hansson O (2013) Plasma tau levels in Alzheimer’s disease. Alzheimers Res Ther 5:9PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Chiu MJ, Chen YF, Chen TF, Yang SY, Yang FP, Tseng TW, Chieh JJ, Chen JC, Tzen KY, Hua MS, Horng HE (2014) Plasma tau as a window to the brain—negative associations with brain volume and memory function in mild cognitive impairment and early Alzheimer’s disease. Hum Brain Mapp 35:3132–3142PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Kandimalla RJ, Prabhakar S, Wani WY, Kaushal A, Gupta N, Sharma DR, Grover VK, Bhardwaj N, Jain K, Gill KD (2013) CSF p-Tau levels in the prediction of Alzheimer’s disease. Biol Open 2:1119–1124PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Hampel H, Bürger K, Pruessner JC, Zinkowski R, DeBernardis J (2005) Correlation of cerebrospinal fluid levels of tau protein phosphorylated at threonine 231 with rates of hippocampal atrophy in Alzheimer disease. Arch Neurol 62:770–773PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Shekhar S, Kumar R, Rai N, Kumar V, Singh K, Upadhyay AD, Tripathi M, Dwivedi S, Dey AB, Dey S (2016) Estimation of Tau and phosphorylated Tau181 in serum of Alzheimer’s disease and mild cognitive impairment patients. PLoS One 11:e0159099PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Farías G, Pérez P, Slachevsky A, Maccioni RB (2012) Platelet tau pattern correlates with cognitive status in Alzheimer’s disease. J Alzheimers Dis 31:65–69PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Guzmán-Martínez L, Farías GA, Maccioni RB (2012) Emerging noninvasive biomarkers for early detection of Alzheimer’s disease. Arch Med Res 43:663–666PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Geekiyanage H, Chan C (2011) MicroRNA-137/181c regulates serine palmitoyltransferase and in turn amyloid β, novel targets in sporadic Alzheimer’s disease. J Neurosci 31:14820–14830PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Hébert SS, Horré K, Nicolaï L, Papadopoulou AS, Mandemakers W, Silahtaroglu AN, Kauppinen S, Delacourte A, De Strooper B (2008) Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer’s disease correlates with increased BACE1/beta-secretase expression. Proc Natl Acad Sci USA 105:6415–6420PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Sheinerman KS, Tsivinsky VG, Crawford F, Mullan MJ, Abdullah L, Umansky SR (2012) Plasma microRNA biomarkers for detection of mild cognitive impairment. Aging (Albany NY) 4:590–605CrossRefGoogle Scholar
  42. 42.
    Leidinger P, Backes C, Deutscher S, Schmitt K, Mueller SC, Frese K, Haas J, Ruprecht K, Paul F, Stähler C, Lang CJ, Meder B, Bartfai T, Meese E, Keller A (2013) A blood based 12-miRNA signature of Alzheimer disease patients. Genome Biol 14:R78PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Tan L, Yu JT, Tan MS, Liu QY, Wang HF, Zhang W, Jiang T, Tan L (2014) Genome-wide serum microRNA expression profiling identifies serum biomarkers for Alzheimer’s disease. J Alzheimers Dis 40:1017–1027PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Kim DK, Seo MY, Lim S, Kim S, Kim JW, Carroll BJ, Kwon DY, Kwon T, Kang SS (2001) Serum melanotransferrin, p97 as a biochemical marker of Alzheimer’s disease. Neuropsychopharmacology 25:84–90PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Ujiie M, Dickstein DL, Jefferies WA (2002) p97 as a biomarker for Alzheimer disease. Front Biosci 7:e42–e47PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Desrosiers RR, Bertrand Y, Nguyen QT, Demeule M, Gabathuler R, Kennard ML, Gauthier S, Béliveau R (2003) Expression of melanotransferrin isoforms in human serum: relevance to Alzheimer’s disease. Biochem J 374:463–471PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325:201–204PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Ingram DK, Zhu M, Mamczarz J, Zou S, Lane MA, Roth GS, deCabo R (2006) Calorie restriction mimetics: an emerging research field. Aging Cell 5:97–108PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Spindler SR (2010) Caloric restriction: from soup to nuts. Ageing Res Rev 9:324–353PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Chen D, Steele AD, Lindquist S, Guarente L (2005) Increase in activity during calorie restriction requires Sirt1. Science 310:1641PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Li Y, Xu W, McBurney MW, Longo VD (2008) SirT1 inhibition reduces IGFI/IRS-2/Ras/ERK1/2 signaling and protects neurons. Cell Metab 8:38–48PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Michishita E, Park JY, Burneskis JM, Barrett JC, Horikawa I (2005) Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell 16:4623–4635PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Shi T, Wang F, Stieren E, Tong Q (2005) SIRT3, a mitochondrial sirtuins deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes. J Biol Chem 280:13560–13567PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Haigis MC, Sinclair DA (2010) Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol 5:253–295PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Imai S, Armstrong CM, Kaeberlein M, Guarente L (2000) Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403:795–800PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, Leid M, McBurney MW, Guarente L (2004) Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 429:771–776PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, Zhao W, Thiyagarajan M, MacGrogan D, Rodgers JT, Puigserver P, Sadoshima J, Deng H, Pedrini S, Gandy S, Sauve AA, Pasinetti GM (2006) Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem 281:21745–21754PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Patel NV, Gordon MN, Connor KE, Good RA, Engelman RW, Mason J, Morgan DG, Morgan TE, Finch CE (2005) Caloric restriction attenuates Abeta-deposition in Alzheimer transgenic models. Neurobiol Aging 26:995–1000PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Guarente L (2008) Mitochondria–a nexus for aging, calorie restriction, and sirtuins. Cell 132:171–176PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Bonda DJ, Lee HG, Camins A, Pallàs M, Casadesus G, Smith MA, Zhu X (2011) The sirtuin pathway in ageing and Alzheimer disease: mechanistic and therapeutic considerations. Lancet Neurol 10:275–279PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Donmez G, Diana W, Cohen DE, Guarente L (2010) SIRT1 Suppresses β-Amyloid Production by Activating the α-Secretase Gene ADAM10. Cell 142:320–332PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101–112PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Luis CA, Abdullah L, Paris D, Quadros A, Mullan M, Mouzon B, Ait-Ghezala G, Crawford F, Mullan M (2009) Serum beta-amyloid correlates with neuropsychological impairment. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn 16:203–218PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA, Sui G, Armour SM, Puigserver P, Sinclair DA, Tsai LH (2007) SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO J 26:3169–3179PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Albani D, Polito L, Forloni G (2011) Sirtuins as novel targets for Alzheimer’s disease and other neurodegenerative disorders: experimental and genetic evidence. J Alzheimers Dis 19:11–26CrossRefGoogle Scholar
  66. 66.
    Vlassenko AG, Vaishnavi SN, Couture L, Sacco D, Shannon BJ, March RH, Morris JC, Raichle ME, Mintun MA (2010) Spatial correlation between brain aerobic glycolysis and amyloid-beta (Abeta) deposition. Proc Natl Acad Sci USA 107:17763–17767PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Nakahata Y, Kaluzova M, Grimaldi B, Sahar S, Hirayama J, Chen D, Guarente LP, Sassone-Corsi P (2008) The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134:329–340PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Prinzen C, Muller U, Endres K, Fahrenholz F, Postina R (2005) Genomic structure and functional characterization of the human ADAM10 promoter. FASEB J 19:1522–1524PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Julien C, Tremblay C, Emond V, Lebbadi M, Salem N Jr, Bennett DA, Calon F (2009) Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease. J Neuropathol Exp Neurol 68:48–58PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Kumar R, Chaterjee P, Sharma PK, Singh AK, Gupta A, Gill K, Tripathi M, Dey AB, Dey S (2013) Sirtuin1: a promising serum protein marker for early detection of Alzheimer’s disease. PLoS One 8:e61560PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Vousden KH, Prives C (2007) Blinded by the light: the growing complexity of p53. Cell 137:413–431CrossRefGoogle Scholar
  72. 72.
    Budanov AV (2011) Stress-responsive sestrins link p53 with redox regulation and mammalian target of rapamycin signaling. Antioxid Redox Signal 15:1679–1690PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Budanov AV, Lee JH, Karin M (2010) Stressin’ Sestrins take an aging fight. EMBO Mol Med 2:388–400PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Richardson JS, Subbarao KV, Ang LC (1990) Biochemical indices of peroxidation in Alzheimer’s and control brains. Trans Am Soc Neurochem 21:113Google Scholar
  75. 75.
    Yoshikawa T (1993) Free radicals and their scavengers in Parkinson’s disease. Eur Neurol 33:60–68PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Choi SI, Kim BY, Dadakhujaev S, Oh JY, Kim TI, Kim JY, Kim EK (2012) Impaired autophagy and delayed autophagic clearance of transforming growth factor β-induced protein (TGFBI) in granular corneal dystrophy type 2. Autophagy 8:1782–1797PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Kim JR, Lee SR, Chung HJ, Kim S, Baek SH, Kim JH, Kim YS (2003) Identification of amyloid beta-peptide responsive genes by cDNA microarray technology: involvement of RTP801 in amyloid beta-peptide toxicity. Exp Mol Med 35:403–411PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Budanov AV, Karin M (2008) p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134:451–460PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Papadia S, Soriano FX, Leveille F, Martel MA, Dakin KA, Hansen HH, Kaindl A, Sifringer M, Fowler J, Stefovska V, McKenzie G, Craigon M, Corriveau R, Ghazal P, Horsburgh K, Yankner BA, Wyllie DJ, Ikonomidou C, Hardingham GE (2008) Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses. Nat Neurosci 11:476–487PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Jönsson TJ, Lowther WT (2007) The peroxiredoxin repair proteins. Subcell Biochem 44:115–141PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Essler S, Dehne N, Brune B (2009) Role of sestrin2 in peroxide signaling in macrophages. FEBS Lett 583:3531–3535PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Reddy K, Cusack CL, Nnah IC, Khayati K, Saqcena C, Huynh TB, Noggle SA, Ballabio A, Dobrowolski R (2016) Dysregulation of nutrient sensing and CLEARance in presenilin deficiency. Cell Rep 14:2166–2179PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Skovronsky DM, Lee VM, Trojanowski JQ (2006) Neurodegenerative diseases: new concepts of pathogenesis and their therapeutic implications. Annu Rev Pathol 1:151–170PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Uttara B, Singh AV, Zamboni P, Mahajan RT (2009) Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 7:65–74PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Soontornniyomkij V, Soontornniyomkij B, Moore DJ, Gouaux B, Masliah E, Tung S, Vinters HV, Grant I, Achim CL (2012) Antioxidant sestrin-2 redistribution to neuronal soma in human immunodeficiency virus-associated neurocognitive disorders. J Neuroimmune Pharmacol 7:579–590PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Saveljeva S, Cleary P, Mnich K, Ayo A, Pakos-Zebrucka K, Patterson JB, Logue SE, Samali A (2016) Endoplasmic reticulum stress-mediated induction of SESTRIN 2 potentiates cell survival. Oncotarget 7:12254PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Kourtis N, Tavernarakis N (2011) Cellular stress response pathways and ageing: intricate molecular relationships. EMBO J 30:2520–2531PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Park HW, Park H, Ro SH, Jang I, Semple IA, Kim DN, Kim M, Nam M, Zhang D, Yin L, Lee JH (2014) Hepatoprotective role of Sestrin2 against chronic ER stress. Nat Commun 5:4233PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Wurtman R (2015) Biomarkers in the diagnosis and management of Alzheimer’s disease. Metabolism 64:S47–S50PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Joshi YB, Praticò D (2015) The 5-lipoxygenase pathway: oxidative and inflammatory contributions to the Alzheimer’s disease phenotype. Front Cell Neurosci 8:436PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Giannopoulos PF, Joshi YB, Praticò D (2014) Novel lipid signaling pathways in Alzheimer’s disease pathogenesis. Biochem Pharmacol 88:560–564PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Shashank Shekhar, Saroj Kumar Yadav, Nitish Rai, Rahul Kumar, Yudhishthir Yadav, Manjari Tripathi, Aparajit B. Dey, Sharmistha Dey, (2018) 5-LOX in Alzheimer’s Disease: Potential Serum Marker and In Vitro Evidences for Rescue of Neurotoxicity by Its Inhibitor YWCS. Molecular Neurobiology 55 (4):2754-2762PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Nickerson DA, Taylor SL, Fullerton SM, Weiss KM, Clark AG, Stengard JH, Salomaa V, Boerwinkle E, Sing CF (2000) Sequence diversity and large-scale typing of SNPs in the human apolipoprotein E gene. Genome Res 10:1532–1545PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923CrossRefPubMedGoogle Scholar
  95. 95.
    Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 90:1977–1981PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE (2007) Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet 39:17–23PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278:1349–1356PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE (2009) The AlzGene database. Alzheimer Research Forum. http://www.alzgene.org
  99. 99.
    Roses AD (1996) Apolipoprotein E alleles as risk factors in Alzheimer’s disease. Annu Rev Med 47:387–400PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC Jr, Rimmler JB, Locke PA, Conneally PM, Schmader KE, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1994) Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet 7:180–184PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Schapira AHV (1999) Science, medicine, and the future Parkinson’s disease. BMJ 318:311–314PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Esteves AR, Arduíno DM, Swerdlow RH, Oliveira CR, Cardoso SM (2009) Oxidative stress involvement in alpha-synuclein oligomerization in Parkinson’s disease cybrids. Antioxid Redox Signal 11:439–448PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Maswood N, Young J, Tilmont E, Zhang Z, Gash DM, Gerhardt GA, Grondin R, Roth GS, Mattison J, Lane MA, Carson RE, Cohen RM, Mouton PR, Quigley C, Mattson MP, Ingram DK (2004) Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson’s disease. Proc Natl Acad Sci USA 101:18171–18176PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Lin SJ, Ford E, Haigis M, Liszt G, Guarente L (2004) Calorie restriction extends yeast life span by lowering the level of NADH. Genes Dev 18:12–16PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Grasso M, Piscopo P, Confaloni A, Denti MA (2014) Circulating miRNAs as biomarkers for neurodegenerative disorders. Molecules 19:6891–6910PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Nuytemans K, Theuns J, Cruts M (2010) Genetic Etiology of Parkinson Disease Associated with Mutations in the SNCA, PARK2, PINK1, PARK7 and LRRK2 genes: a mutation update. Hum Mutat 31:763–780PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Fiskum G, Starkov A, Polster B (2003) Mitochondrial mechanisms of neural cell death and neuro protective interventions in Parkinson’s disease. Ann N Y Acad Sci 991:111–119PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Greenamyre JT, Betarbet R, Sherer TB (2003) The rotenone model of Parkinson’s disease: genes, environment and mitochondria. Parkinsonism Relat Disord 9:S59–S64PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795CrossRefGoogle Scholar
  110. 110.
    Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atarés B, Llorens V, Gomez Tortosa E, del Ser T, Muñoz DG, de Yebenes JG (2004) The new mutation, E46K, of α-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55:164–173PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Lee HJ, Patel S, Lee SJ (2005) Intravascular localization and exocytosis of alpha-synuclein and its aggregates. J Neurosci 25:6016–6024PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Marques O, Outeiro TF (2012) Alpha-synuclein: from secretion to dysfunction and death. Cell Death Dis 3:e350PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Nakai M, Fujita M, Waragai M, Sugama S, Wei J, Akatsu H, Ohtaka-Maruyama C, Okado H, Hashimoto M (2007) Expression of alpha-synuclein, a presynaptic protein implicated in Parkinson’s disease, in erythropoietic lineage. Biochem Biophys Res Commun 358:104–110PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Alvarez-Erviti L, Seow Y, Schapira AH, Gardiner C, Sargent IL, Wood MJ, Cooper JM (2011) Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Neurobiol Dis 42:360–367PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Danzer KM, Kranich LR, Ruf WP, Cagsal-Getkin O, Winslow AR, Zhu L, Vanderburg CR, McLean PJ (2012) Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener 7:42PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Shi M, Liu C, Cook TJ, Bullock KM, Zhao Y, Ginghina C, Li Y, Aro P, Dator R, He C, Hipp MJ, Zabetian CP, Peskind ER, Hu SC, Quinn JF, Galasko DR, Banks WA, Zhang J (2014) Plasma exosomal alpha-synuclein is likely CNS-derived and increased in Parkinson’s disease. Acta Neuropathol 128:639–650PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Donadio V, Incensi A, Leta V, Giannoccaro MP, Scaglione C, Martinelli P, Capellari S, Avoni P, Baruzzi A, Liguori R (2014) Skin nerve alpha-synuclein deposits: a biomarker for idiopathic Parkinson disease. Neurology 82:1362–1369PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Ohrfelt A, Grognet P, Andreasen N, Wallin A, Vanmechelen E, Blennow K, Zetterberg H (2009) Cerebrospinal fluid alpha-synuclein in neurodegenerative disorders-a marker of synapse loss? Neurosci Lett 450:332–335PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Park MJ, Cheon SM, Bae HR, Kim SH, Kim JW (2011) Elevated levels of alpha-synuclein oligomer in the cerebrospinal fluid of drug-naive patients with Parkinson’s disease. J Clin Neurol 7:215–222PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Mollenhauer B, Locascio JJ, Schulz-Schaeffer W, Sixel-Doring F, Trenkwalder C, Schlossmacher MG (2011) Alpha-Synuclein and tau concentrations in cerebrospinal fluid of patients presenting with parkinsonism: a cohort study. Lancet Neurol 10:230–240PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Mollenhauer B, Trautmann E, Taylor P, Manninger P, Sixel-Doring F, Ebentheuer J, Trenkwalder C, Schlossmacher MG (2013) Total CSF alpha-synuclein is lower in de novo Parkinson patients than in healthy subjects. Neurosci Lett 532:44–48PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Parnetti L, Chiasserini D, Bellomo G, Giannandrea D, De Carlo C, Qureshi MM, Ardah MT, Varghese S, Bonanni L, Borroni B, Tambasco N, Eusebi P, Rossi A, Onofrj M, Padovani A, Calabresi P, El-Agnaf O (2011) Cerebrospinal fluid Tau/alpha-synuclein ratio in Parkinson’s disease and degenerative dementias. Mov Disord 26:1428–1435PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Tokuda T, Salem SA, Allsop D, Mizuno T, Nakagawa M, Qureshi MM, Locascio JJ, Schlossmacher MG, El-Agnaf OM (2006) Decreased alpha-synuclein in cerebrospinal fluid of aged individuals and subjects with Parkinson’s disease. Biochem Biophys Res Commun 349:162–166PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Hall S, Ohrfelt A, Constantinescu R, Andreasson U, Surova Y, Bostrom F, Nilsson C, Håkan W, Decraemer H, Någga K, Minthon L, Londos E, Vanmechelen E, Holmberg B, Zetterberg H, Blennow K, Hansson O (2012) Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders. Arch Neurol 69:1445–1452PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Hong Z, Shi M, Chung KA, Quinn JF, Peskind ER, Galasko D, Jankovic J, Zabetian CP, Leverenz JB, Baird G, Montine TJ, Hancock AM, Hwang H, Pan C, Bradner J, Kang UJ, Jensen PH, Zhang J (2010) DJ-1 and alpha-synuclein in human cerebrospinal fluid as biomarkers of Parkinson’s disease. Brain 133:713–726PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Wang Y, Shi M, Chung KA, Zabetian CP, Leverenz JB, Berg D, Srulijes K, Trojanowski JQ, Lee VM, Siderowf AD, Hurtig H, Litvan I, Schiess MC, Peskind ER, Masuda M, Hasegawa M, Lin X, Pan C, Galasko D, Goldstein DS, Jensen PH, Yang H, Cain KC, Zhang J (2012) Phosphorylated alpha-synuclein in Parkinson’s disease. Sci Transl Med 4:121ra20PubMedPubMedCentralGoogle Scholar
  127. 127.
    Shi M, Zabetian CP, Hancock AM, Ginghina C, Hong Z, Yearout D, Chung KA, Quinn JF, Peskind ER, Galasko D, Jankovic J, Leverenz JB, Zhang J (2010) Significance and confounders of peripheral DJ-1 and alpha-synuclein in Parkinson’s disease. Neurosci Lett 480:78–82PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Borghi R, Marchese R, Negro A, Marinelli L, Forloni G, Zaccheo D, Abbruzzese G, Tabaton M (2000) Full length alpha-synuclein is present in cerebrospinal fluid from Parkinson’s disease and normal subjects. Neurosci Lett 287:65–67PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Jakowec MW, Petzinger GM, Sastry S, Donaldson DM, McCormack A, Langston JW (1998) The native form of alpha-synuclein is not found in the cerebrospinal fluid of patients with Parkinson’s disease or normal controls. Neurosci Lett 253:13–16PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Stewart T, Sossi V, Aasly JO, Wszolek ZK, Uitti RJ, Hasegawa K, Yokoyama T, Zabetian CP, Leverenz JB, Stoessl AJ, Wang Y, Ginghina C, Liu C, Cain KC, Auinger P, Kang UJ, Jensen PH, Shi M, Zhang J (2015) Phosphorylated alpha-synuclein in Parkinson’s disease: correlation depends on disease severity. Acta Neuropathol Commun 3:7PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Besong-Agbo D, Wolf E, Jessen F, Oechsner M, Hametner E, Poewe W, Reindl M, Oertel WH, Noelker C, Bacher M, Dodel R (2013) Naturally occurring alpha-synuclein autoantibody levels are lower in patients with Parkinson disease. Neurology 80:169–175PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Duran R, Barrero FJ, Morales B, Luna JD, Ramirez M, Vives F (2010) Plasma alpha-synuclein in patients with Parkinson’s disease with and without treatment. Mov Disord 25:489–493PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Lee PH, Lee G, Park HJ, Bang OY, Joo IS, Huh K (2006) The plasma alpha-synuclein levels in patients with Parkinson’s disease and multiple system atrophy. J Neural Transm 113:1435–1439PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Li QX, Mok SS, Laughton KM, McLean CA, Cappai R, Masters CL, Culvenor JG, Horne MK (2007) Plasma alpha-synuclein is decreased in subjects with Parkinson’s disease. Exp Neurol 204:583–588PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Foulds PG, Mitchell JD, Parker A, Turner R, Green G, Diggle P, Hasegawa M, Taylor M, Mann D, Allsop D (2011) Phosphorylated alpha-synuclein can be detected in blood plasma and is potentially a useful biomarker for Parkinson’s disease. FASEB J 25:4127–4137PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Mata IF, Shi M, Agarwal P, Chung KA, Edwards KL, Factor SA, Galasko DR, Ginghina C, Griffith A, Higgins DS, Kay DM, Kim H, Leverenz JB, Quinn JF, Roberts JW, Samii A, Snapinn KW, Tsuang DW, Yearout D, Zhang J, Payami H, Zabetian CP (2010) SNCA variant associated with Parkinson disease and plasma alpha-synuclein level. Arch Neurol 67:1350–1356PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Gorostidi A, Bergareche A, Ruiz-Martinez J, Marti-Masso JF, Cruz M, Varghese S, Qureshi MM, Alzahmi F, Al-Hayani A, López de Munáin A, El-Agnaf OM (2012) Alpha-synuclein levels in blood plasma from LRRK2 mutation carriers. PLoS One 7:e52312PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Miller DW, Hague SM, Clarimon J, Baptista M, Gwinn-Hardy K, Cookson MR, Singleton AB (2004) Alpha-synuclein in blood and brain from familial Parkinson disease with SNCA locus triplication. Neurology 62:1835–1838PubMedCrossRefPubMedCentralGoogle Scholar
  139. 139.
    Abd-Elhadi S, Honig A, Simhi-Haham D, Schechter M, Linetsky E, Ben-Hur T, Sharon R (2015) Total and proteinase K-resistant alpha-synuclein levels in erythrocytes, determined by their ability to bind phospholipids, Associate with Parkinson’s Disease. Sci Rep 5:11120PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Wang X, Yu S, Li F, Feng T (2015) Detection of alpha-synuclein oligomers in red blood cells as a potential biomarker of Parkinson’s disease. Neurosci Lett 599:115–119PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Devic I, Hwang H, Edgar JS, Izutsu K, Presland R, Pan C, Goodlett DR, Wang Y, Armaly J, Tumas V, Zabetian CP, Leverenz JB, Shi M, Zhang J (2011) Salivary alpha-synuclein and DJ-1: potential biomarkers for Parkinson’s disease. Brain 134:e178PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Stewart T, Sui YT, Gonzalez-Cuyar LF, Wong DT, Akin DM, Tumas V, Aasly J, Ashmore E, Aro P, Ginghina C, Korff A, Zabetian CP, Leverenz JB, Shi M, Zhang J (2014) Cheek cell-derived alpha-synuclein and DJ-1 do not differentiate Parkinson’s disease from control. Neurobiol Aging 35:418–420PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Al-Nimer MS, Mshatat SF, Abdulla HI (2014) Saliva alpha-synuclein and a high extinction coefficient protein: a novel approach in assessment biomarkers of Parkinson’ disease. N Am J Med Sci 6:633–637PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:256–259PubMedCrossRefPubMedCentralGoogle Scholar
  145. 145.
    Lin X, Cook TJ, Zabetian CP, Leverenz JB, Peskind ER, Hu S-C, Cain KC, Pan C, Edgar JS, Goodlett DR, Racette BA, Checkoway H, Montine TJ, Shi M, Zhang J (2012) DJ-1 isoforms in whole blood as potential biomarkers of Parkinson disease. Sci Rep 2:954PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Chahine LM, Stern MB, Chen-Plotkin A (2014) Blood-based biomarkers for Parkinson’s disease. Parkinsonism Relat Disord 1:S99–S103CrossRefGoogle Scholar
  147. 147.
    Schwarzschild MA, Schwid SR, Marek K, Watts A, Lang AE, Oakes D, Shoulson I, Ascherio A, Parkinson Study Group PRECEPT Investigators, Hyson C, Gorbold E, Rudolph A, Kieburtz K, Fahn S, Gauger L, Goetz C, Seibyl J, Forrest M, Ondrasik J (2008) Serum urate as a predictor of clinical and radiographic progression in Parkinson disease. Arch Neurol 65:716–723CrossRefGoogle Scholar
  148. 148.
    Qiang JK, Wong YC, Siderowf A, Hurtig HI, Xie SX, Lee VM, Trojanowski JQ, Yearout DB, Leverenz J, Montine TJ, Stern M, Mendick S, Jennings D, Zabetian C, Marek K, Chen-Plotkin AS (2013) Plasma apolipoprotein A1 as a biomarker for Parkinson disease. Ann Neurol 74:119–127PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Gao X, Simon KC, Schwarzschild MA, Ascherio A (2012) Prospective study of statin use and risk of Parkinson disease. Arch Neurol 69:380–384PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Lee YC, Lin CH, Wu RM, Lin MS, Lin JW, Chang CH, Lai MS (2013) Discontinuation of statin therapy associates with Parkinson disease: A population-based study. Neurology 81:410–416PubMedCrossRefPubMedCentralGoogle Scholar
  151. 151.
    Margis R, Margis R, Rieder CR (2011) Identification of blood microRNAs associated to Parkinson’s disease. J Biotechnol 152:96–101PubMedCrossRefPubMedCentralGoogle Scholar
  152. 152.
    Khoo SK, Petillo D, Kang UJ, Resau JH, Berryhill B, Linder J, Forsgren L, Neuman LA, Tan AC (2012) Plasma-based circulating MicroRNA biomarkers for Parkinson’s disease. J Park Dis 2:321–331Google Scholar
  153. 153.
    Botta-Orfila T, Morató X, Compta Y, Lozano JJ, Falgàs N, Valldeoriola F, Pont-Sunyer C, Vilas D, Mengual L, Fernández M, Molinuevo JL, Antonell A, Martí MJ, Fernández-Santiago R, Ezquerra M (2014) Identification of blood serum micro-RNAs associated with idiopathic and LRRK2 Parkinson’s disease. J Neurosci Res 92:1071–1077PubMedCrossRefPubMedCentralGoogle Scholar
  154. 154.
    Pankratz N, Nichols WC, Uniacke SK, Halter C, Rudolph A, Shults C, Conneally PM, Foroud T, Parkinson Study Group (2003) Significant linkage of Parkinson disease to chromosome 2q36–37. Am J Hum Genet 72:1053–1057PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Shimura H, Hattori N, Si K, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T (2000) Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nature 25:302–305Google Scholar
  156. 156.
    Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, González-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160PubMedCrossRefPubMedCentralGoogle Scholar
  157. 157.
    Le WD, Xu P, Jankovic J, Jiang H, Appel SH, Smith RG, Vassilatis DK (2003) Mutations in NR4A2 associated with familial Parkinson disease. Nat Genet 33:85–89PubMedCrossRefPubMedCentralGoogle Scholar
  158. 158.
    Le WD, Appel SH (2004) Mutation genes responsible for Parkinson disease. Curr Opin Pharmacol 4:79–84PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Sharmistha Dey
    • 1
  • Nitish Rai
    • 1
  • Shashank Shekhar
    • 1
  • Amrendra Pratap Singh
    • 1
  • Vertica Agnihotri
    • 1
  1. 1.Department of BiophysicsAll India Institute of Medical SciencesNew DelhiIndia

Personalised recommendations