Parkinson hastalığı (PH), popülasyonun önemli bir kısmını etkileyen, ilerleyici özellikte, nörodejeneratif bir hastalıktır. Çok faktörlü oluşum mekanizmaları tam olarak aydınlatılamadığı için patogenezi üzerinde birçok çalışma yürütülmektedir. PH gelişiminde en önemli risk faktörünün yaş olduğu ve hastalığın insidansının yaş ile arttığı bilinmektedir. Pestisitler, herbisitler ve ağır metaller gibi çevresel kirleticilere maruziyet de PH ile ilişkilendirilmiştir. Hastalığın patogenezinde rol oynayan genler arasında Parkin (PARK2), PTEN ile indüklenen kinaz (PINK1; PARK6), PH proteini 7 (DJ-1, PARK7), α-sinüklein (PARK1/4) ve lösince zengin tekrarlı kinaz 2 (LRRK2, PARK8) sayılabilir. Endoplazmik retikulum (ER) stresi; PH, Alzheimer hastalığı, Huntington hastalığı, amyotrofik lateral skleroz ve obezite gibi birçok hastalıkla ilişkilidir ve son yıllarda üzerinde en çok çalışılan konulardan biri olmuştur. PH'de nöronal ölüm, oksidatif stres ve mitokondriyal disfonksiyonla ER stresinin, nörodejenerasyona yol açtığı gözlemlenmiştir. Çalışmalara göre oluşan ER stresinin düzeyi çok önemlidir, PH patogenezinde doğrudan hastalık oluşturma potansiyeline sahip olmamakla beraber nörodejenerasyona ortam hazırladığı ve ilerlemesini sağladığı görülmüştür. ER stresinin, in vitro/in vivo şartlarda PH modelleri üzerinde aydınlatılması ve ER stresi mekanizmalarının incelenmesinin, hastalığın tedavisinde etkili yeni nöroprotektif ajanların geliştirilmesinde büyük önemi olacaktır. Bu derlemede; PH, ER stresi, ER stres yolağında görev alan proteinler, katlanmamış protein yanıtı ve ER stresi ile PH arasındaki ilişkinin incelenmesi amaçlanmıştır.
Anahtar Kelimeler: Endoplazmik retikulum stresi; Parkinson hastalığı; nörodejenerasyon
Parkinson's disease (PD) is a progressive neurodegenerative disease affecting a significant population. Since multi-factor formation mechanisms are not fully elucidated, many studies are being conducted on its pathogenesis. It is known that age is the most important risk factor in the development of PD and its incidence increases with age. Exposure to environmental pollutants such as pesticides, herbicides and heavy metals were also associated with PD. Among the genes involved in the pathogenesis, Parkin (PARK2), PTEN-induced kinase (PINK1; PARK6), PD protein 7 (DJ-1, PARK7), α-synuclein (PARK1/4) and leucine-rich repeat kinase 2 (LRRK2, PARK8) take place. Endoplasmic reticulum (ER) stress, a highly investigated subject in the last years, is associated with many diseases such as PD, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and obesity. It has been observed that neuronal death, oxidative stress, mitochondrial dysfunction and ER stress lead to neurodegeneration in PD. According to these studies, the level of ER stress is very important. Although it does not have potential to have a direct effect on the pathogenesis of PD, it has been observed that it prepares the environment for neurodegeneration and ensures its progression. The elucidation of ER stress on PD models and investigation of ER stress mechanisms will be of great importance in the development of new effective neuroprotective agents in treatment. In this review, we aimed to investigate and give information about PD, ER stress, proteins involved in the ER stress pathway, unfolded protein response (UPR) and the relationship between ER stress and PD.
Keywords: Endoplasmic reticulum stres; Parkinson's disease; neurodegeneration
- Mercado G, Valdés P, Hetz C. An ERcentric view of Parkinson's disease. Trends Mol Med. 2013;19(3):165-75. [Crossref] [PubMed]
- Zeng XS, Geng WS, Jia JJ, Chen L, Zhang PP. Cellular and molecular basis of neurodegeneration in Parkinson disease. Front Aging Neurosci. 2018;10:109. [Crossref] [PubMed] [PMC]
- DeMaagd G, Philip A. Parkinson's disease and its management: Part 1: disease entity, risk factors, pathophysiology, clinical presentation, and diagnosis. P T. 2015;40(8):504-32. [PubMed] [PMC]
- Omura T, Kaneko M, Okuma Y, Matsubara K, Nomura Y. Endoplasmic reticulum stress and Parkinson's disease: the role of HRD1 in averting apoptosis in neurodegenerative disease. Oxid Med Cell Longev. 2013;2013: 239854. [Crossref] [PubMed] [PMC]
- Roussel BD, Kruppa AJ, Miranda E, Crowther DC, Lomas DA, Marciniak SJ. Endoplasmic reticulum dysfunction in neurological disease. Lancet Neurol. 2013;12(1):105-18. [Crossref] [PubMed]
- Kalia LV, Lang AE. Parkinson's disease. Lancet. 2015;386(9996):896-912. [Crossref] [PubMed]
- Calì T, Ottolini D, Brini M. Mitochondria, calcium, and endoplasmic reticulum stress in Parkinson's disease. Biofactors. 2011;37(3): 228-40. [Crossref] [PubMed]
- Türk Nöroloji Derneği [İnternet]. Copyright © 2020 Türk Nöroloji Derneği [Erişim tarihi: 14.9.2020]. Dünya Beyin Günü basın bülteni. Erişim linki: [Link]
- Jankovic J. Levodopa strengths and weaknesses. Neurology. 2002;58(4 Suppl 1):S19-32. [Crossref] [PubMed]
- Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA. 2014;311(16):1670-83. [Crossref] [PubMed]
- Quik M. Smoking, nicotine and Parkinson's disease. Trends Neurosci. 2004;27(9):561-8. [Crossref] [PubMed]
- Ross GW, Abbott RD, Petrovitch H, Morens DM, Grandinetti A, Tung KH, et al. Association of coffee and caffeine intake with the risk of Parkinson disease. JAMA. 2000;283(20): 2674-9. [Crossref] [PubMed]
- de Lau LM, Breteler MM. Epidemiology of Parkinson's disease. Lancet Neurol. 2006;5(6):525-35. [Crossref] [PubMed]
- Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science. 1983;219(4587):979-80. [Crossref] [PubMed]
- Lai BC, Marion SA, Teschke K, Tsui JK. Occupational and environmental risk factors for Parkinson's disease. Parkinsonism Relat Disord. 2002;8(5):297-309. [Crossref] [PubMed]
- Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 1997;276 (5321):2045-7. [Crossref] [PubMed]
- Heman-Ackah SM, Manzano R, Hoozemans JJM, Scheper W, Flynn R, Haerty W, et al. Alpha-synuclein induces the unfolded protein response in Parkinson's disease SNCA triplication iPSC-derived neurons. Hum Mol Genet. 2017;26(22):4441-50. [Crossref] [PubMed] [PMC]
- Pupyshev AB, Korolenko TA, Akopyan AA, Amstislavskaya TG, Tikhonova MA. Suppression of autophagy in the brain of transgenic mice with overexpression of А53Т-mutant α-synuclein as an early event at synucleinopathy progression. Neurosci Lett. 2018;672:140-4. [Crossref] [PubMed]
- Zharikov AD, Cannon JR, Tapias V, Bai Q, Horowitz MP, Shah V, et al. shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson's disease model. J Clin Invest. 2015;125(7):2721-35. [Crossref] [PubMed] [PMC]
- Lutz AK, Exner N, Fett ME, Schlehe JS, Kloos K, Lämmermann K, et al. Loss of parkin or PINK1 function increases Drp1-dependent mitochondrial fragmentation. J Biol Chem. 2009; 284(34):22938-51. [Crossref] [PubMed] [PMC]
- Ferreira M, Massano J. An updated review of Parkinson's disease genetics and clinicopathological correlations. Acta Neurol Scand. 2017; 135(3):273-84. [Crossref] [PubMed]
- Volpicelli-Daley LA, Abdelmotilib H, Liu Z, Stoyka L, Daher JP, Milnerwood AJ, et al. G2019S-LRRK2 expression augments α-synuclein sequestration into inclusions in neurons. J Neurosci. 2016;36(28):7415-27. [Crossref] [PubMed] [PMC]
- Yoon JH, Mo JS, Kim MY, Ann EJ, Ahn JS, Jo EH, et al. LRRK2 functions as a scaffolding kinase of ASK1-mediated neuronal cell death. Biochim Biophys Acta Mol Cell Res. 2017; 1864(12):2356-68. [Crossref] [PubMed]
- Bonifati V, Rizzu P, Squitieri F, Krieger E, Vanacore N, van Swieten JC, et al. DJ-1( PARK7), a novel gene for autosomal recessive, early onset parkinsonism. Neurol Sci. 2003;24(3):159-60. [Crossref] [PubMed]
- 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(11):e327. [Crossref] [PubMed] [PMC]
- Batelli S, Invernizzi RW, Negro A, Calcagno E, Rodilossi S, Forloni G, et al. The Parkinson's disease-related protein DJ-1 protects dopaminergic neurons in vivo and cultured cells from alpha-synuclein and 6-hydroxydopamine toxicity. Neurodegener Dis. 2015; 15(1):13-23. [Crossref] [PubMed]
- Ablat N, Lv D, Ren R, Xiaokaiti Y, Ma X, Zhao X, et al. Neuroprotective effects of a standardized flavonoid extract from safflower against a rotenone-induced rat model of Parkinson's disease. Molecules. 2016;21(9):1107. [Crossref] [PubMed] [PMC]
- Tang FL, Erion JR, Tian Y, Liu W, Yin DM, Ye J, et al. VPS35 in dopamine neurons is required for endosome-to-golgi retrieval of Lamp2a, a receptor of chaperone-mediated autophagy that is critical for α-synuclein degradation and prevention of pathogenesis of Parkinson's disease. J Neurosci. 2015; 35(29):10613-28. [Crossref] [PubMed] [PMC]
- Chen X, Kordich JK, Williams ET, Levine N, Cole-Strauss A, Marshall L, et al. Parkinson's disease-linked D620N VPS35 knockin mice manifest tau neuropathology and dopaminergic neurodegeneration. Proc Natl Acad Sci U S A. 2019;116(12):5765-74. [Crossref] [PubMed] [PMC]
- Wang W, Wang X, Fujioka H, Hoppel C, Whone AL, Caldwell MA, et al. Parkinson's disease-associated mutant VPS35 causes mitochondrial dysfunction by recycling DLP1 complexes. Nat Med. 2016;22(1):54-63. [Crossref] [PubMed] [PMC]
- Kurman Y. Parkinson hastalığı ve ilişkili olduğu genler [Parkinson disease and associated genes]. Düzce Üniversitesi Bilim ve Teknoloji Dergisi. 2018;6(1):231-9. [Crossref]
- Migdalska-Richards A, Daly L, Bezard E, Schapira AH. Ambroxol effects in glucocerebrosidase and α-synuclein transgenic mice. Ann Neurol. 2016;80(5):766-75. [Crossref] [PubMed] [PMC]
- Burbulla LF, Song P, Mazzulli JR, Zampese E, Wong YC, Jeon S, et al. Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease. Science. 2017;357(6357):1255-61. [Crossref] [PubMed] [PMC]
- Post MR, Lieberman OJ, Mosharov EV. Can interactions between α-synuclein, dopamine and calcium explain selective neurodegeneration in Parkinson's disease? Front Neurosci. 2018;12:161. [Crossref] [PubMed] [PMC]
- Westrate LM, Lee JE, Prinz WA, Voeltz GK. Form follows function: the importance of endoplasmic reticulum shape. Annu Rev Biochem. 2015;84:791-811. [Crossref] [PubMed]
- Schwarz DS, Blower MD. The endoplasmic reticulum: structure, function and response to cellular signaling. Cell Mol Life Sci. 2016; 73(1):79-94. [Crossref] [PubMed] [PMC]
- Görlach A, Klappa P, Kietzmann T. The endoplasmic reticulum: folding, calcium homeostasis, signaling, and redox control. Antioxid Redox Signal. 2006;8(9-10):1391-418. [Crossref] [PubMed]
- Köse Ö, Erkekoğlu P, Özyurt B, Koçer Gümüşel B. Endoplazmik retikulum stresi ve obezite ilişkisine genel bir bakış [An overview of the endoplasmic reticulum stress and interrelation with obesity: review]. Turkiye Klinikleri J Pharm Sci. 2017;6(2):77-93. [Crossref]
- Timmins JM, Ozcan L, Seimon TA, Li G, Malagelada C, Backs J, et al. Calcium/ calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways. J Clin Invest. 2009;119(10): 2925-41. [Crossref] [PubMed] [PMC]
- Marciniak SJ, Ron D. Endoplasmic reticulum stress signaling in disease. Physiol Rev. 2006;86(4):1133-49. [Crossref] [PubMed]
- Nishikawa S, Brodsky JL, Nakatsukasa K. Roles of molecular chaperones in endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD). J Biochem. 2005;137(5):551-5. [Crossref] [PubMed]
- Tatar M, Tatar T. Endoplazmik retikulum stresi ve ilişkili hastalıklar [Endoplasmic reticulum stress and related diseases]. Osmangazi Tıp Dergisi. 2019;41(3):294-303. [Link]
- Naidoo N. The endoplasmic reticulum stress response and aging. Rev Neurosci. 2009; 20(1):23-37. [Crossref] [PubMed]
- Sarvani C, Sireesh D, Ramkumar KM. Unraveling the role of ER stress inhibitors in the context of metabolic diseases. Pharmacol Res. 2017;119:412-21. [Crossref] [PubMed]
- Tsujii S, Ishisaka M, Hara H. Modulation of endoplasmic reticulum stress in Parkinson's disease. Eur J Pharmacol. 2015;765:154-6. [Crossref] [PubMed]
- Gardner RG, Swarbrick GM, Bays NW, Cronin SR, Wilhovsky S, Seelig L, et al. Endoplasmic reticulum degradation requires lumen to cytosol signaling. Transmembrane control of Hrd1p by Hrd3p. J Cell Biol. 2000;151(1):69-82. [Crossref] [PubMed] [PMC]
- Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010;140(6):900-17. [Crossref] [PubMed] [PMC]
- Szegezdi E, Logue SE, Gorman AM, Samali A. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 2006;7(9): 880-5. [Crossref] [PubMed] [PMC]
- Barone MV, Crozat A, Tabaee A, Philipson L, Ron D. CHOP (GADD153) and its oncogenic variant, TLS-CHOP, have opposing effects on the induction of G1/S arrest. Genes Dev. 1994;8(4):453-64. [Crossref] [PubMed]
- Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT, Remotti H, et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev. 1998;12(7):982-95. [Crossref] [PubMed] [PMC]
- Credle JJ, Forcelli PA, Delannoy M, Oaks AW, Permaul E, Berry DL, et al. α-Synuclein-mediated inhibition of ATF6 processing into COPII vesicles disrupts UPR signaling in Parkinson's disease. Neurobiol Dis. 2015;76:112-25. [Crossref] [PubMed]
- Valdés P, Mercado G, Vidal RL, Molina C, Parsons G, Court FA, et al. Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1. Proc Natl Acad Sci U S A. 2014;111(18):6804-9. [Crossref] [PubMed] [PMC]
- Egawa N, Yamamoto K, Inoue H, Hikawa R, Nishi K, Mori K, et al. The endoplasmic reticulum stress sensor, ATF6α, protects against neurotoxin-induced dopaminergic neuronal death. J Biol Chem. 2011;286(10):7947-57. [Crossref] [PubMed] [PMC]
- Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, Bhullar B, et al. Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science. 2006;313(5785):324-8. [Crossref] [PubMed] [PMC]
- Hoozemans JJ, van Haastert ES, Eikelenboom P, de Vos RA, Rozemuller JM, Scheper W. Activation of the unfolded protein response in Par kinson's disease. Biochem Biophys Res Commun. 2007;354(3):707-11. [Crossref] [PubMed]
- Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell. 2001;105(7):891-902. [Crossref] [PubMed]
- Dukes AA, Van Laar VS, Cascio M, Hastings TG. Changes in endoplasmic reticulum stress proteins and aldolase A in cells exposed to dopamine. J Neurochem. 2008;106(1):333-46. [Crossref] [PubMed] [PMC]
- Sado M, Yamasaki Y, Iwanaga T, Onaka Y, Ibuki T, Nishihara S, et al. Protective effect against Parkinson's disease-related insults through the activation of XBP1. Brain Res. 2009;1257:16-24. [Crossref] [PubMed]
- Silva RM, Ries V, Oo TF, Yarygina O, Jackson-Lewis V, Ryu EJ, et al. CHOP/GADD153 is a mediator of apoptotic death in substantia nigra dopamine neurons in an in vivo neurotoxin model of parkinsonism. J Neurochem. 2005;95(4):974-86. [Crossref] [PubMed] [PMC]
- Colla E, Jensen PH, Pletnikova O, Troncoso JC, Glabe C, Lee MK. Accumulation of toxic α-synuclein oligomer within endoplasmic reticulum occurs in α-synucleinopathy in vivo. J Neurosci. 2012;32(10):3301-5. [Crossref] [PubMed] [PMC]
- Colla E, Coune P, Liu Y, Pletnikova O, Troncoso JC, Iwatsubo T, et al. Endoplasmic reticulum stress is important for the manifestations of α-synucleinopathy in vivo. J Neurosci. 2012; 32(10):3306-20. [Crossref] [PubMed] [PMC]
- Holtz WA, O'Malley KL. Parkinsonian mimetics induce aspects of unfolded protein response in death of dopaminergic neurons. J Biol Chem. 2003;278(21):19367-77. [Crossref] [PubMed]
- Uehara T, Nakamura T, Yao D, Shi ZQ, Gu Z, Ma Y, et al. S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature. 2006;441(7092):513-7. [Crossref] [PubMed]
- Fouillet A, Levet C, Virgone A, Robin M, Dourlen P, Rieusset J, et al. ER stress inhibits neuronal death by promoting autophagy. Autophagy. 2012;8(6):915-26. [Crossref] [PubMed] [PMC]
- Ryu EJ, Harding HP, Angelastro JM, Vitolo OV, Ron D, Greene LA. Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson's disease. J Neurosci. 2002;22(24):10690-8. [Crossref] [PubMed] [PMC]
.: Process List