Nörodejeneratif Hastalıklarda Katlanmamış Protein Cevabının Tedavi Edici Potansiyeli

Öz

Endoplazmik retikulum ER sekretuvar veya membran proteinlerin sentezinden, salgılanmasından, lipid metabolizmasından ve Ca2+’un depolanmasından sorumludur. Hipoksi, oksidatif stres, glukoz yoksunluğu, viral enfeksiyonlar ve ortamın sıcaklığı gibi hem fizyolojik hem de patolojik stres zorlama koşulları, yanlış katlanmış ya da katlanmamış proteinlerin ER lümeninde birikmesine neden olur. ER dengesinin bozulmasıyla ER stresi adı verilen olay meydana gelir. Hücreler normal durumlarına tekrar kavuşmak için strese karşı “katlanmamış protein cevabı Unfolded Protein Response, UPR ” adı verilen sinyal yolağını aktif hale getirirler. UPR sinyali genel protein translasyonunu sentezi azaltarak ER lümeninde biriken protein yükünü azaltmayı hedefler. Ayrıca kontrolünde yer alan moleküler şaperonların refakatçiler transkripsiyonunu artırarak katlanmamış proteinlerin uygun bir şekilde katlanmalarını sağlar. Hafif ER stresi varlığında UPR, hücreyi koruyucu yönde etkilerken, uzun süren ve şiddetli ER stresi koşullarında hücreyi ölüme götüren, hücre kaderini belirleyen anahtar sinyal yolağıdır. Apoptozu tetiklediği durumlarda hastalıkların ortaya çıkması kaçınılmazdır. Özellikle son yapılan çalışmalarda, beyinin spesifik bölgelerinde protein birikimine bağlı gelişen nörodejeneratif hastalıklar ER stresi ile ilişkilendirilmektedir. Dolayısıyla UPR’de önemli rolleri olan moleküler şaperonlara benzer kimyasal şaperonların, ER stresine bağlı gelişen hastalıklarda tedavi edici potansiyelleri tartışılmaktadır. Bu derlemede, nörodejeneratif hastalıklarda ER stresi ve UPR’nin rolü ve bu sinyal yolaklarının olası tedavi edici mekanizmaları, güncel literatüre bağlı olarak değerlendirilmektedir

Anahtar Kelimeler

• Katlanmamış protein cevabı, Nörodejeneratif hastalıklar, Endoplazmik retikulum

Therapeutic Potential of Unfolded Protein Response in Neurodegenerative Diseases

Abstract

The endoplasmic reticulum ER is responsible for lipid metabolism, Ca2+ storage and synthesis and secretion of secretory or membrane proteins. Both physiological and pathological stress conditions including hypoxia, oxidative stress, glucose deprivation, viral infections and ambient temperature cause accumulation of unfolded or misfolded proteins in the ER lumen. When ER homeostasis is impaired, a condition called ER stress occurs. Cells activate the signaling pathway called the Unfolded Protein Response UPR to regain their normal state. The UPR signal aims to reduce the protein burden accumulated in the ER lumen by reducing overall protein translation. It also allows the molecular chaperones to fold the unfolded proteins appropriately by increasing their transcription. In the presence of mild ER stress, the UPR effects cells in a protective way while it is the key signaling pathway that determines the cell destiny and leads to cell death under prolonged and severe ER stress conditions. It is inevitable for diseases to occur when apoptosis is triggered. Protein accumulation in the specific regions of the brain in neurodegenerative diseases have been linked to ER stress in recent studies. The therapeutic potentials of chemical chaperones similar to molecular chaperones, which have important roles in UPR, have therefore attracted interest. In this review, the role of ER stress and the UPR in neurodegenerative diseases and the possible therapeutic mechanisms of these signaling pathways have been evaluated based on the current literature

Keywords

• Unfolded protein response, Neurodegenerative diseases, Endoplasmic reticulum

References

1. 1. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Görgün C, Glimcher LH, Hotamıslıgil GS. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004; 306(5695): 457-61.
2. 2. Biason-Lauber A, Lang-Muritano M, Vaccora T, Schoenle EJ. Loss of kinase activity in a patient with Wolcott-Rallison syndrome caused by a novel mutation in the EIF2AK3 gene. Diabetes 2002; 51(7): 2301-5.
3. 3. Lawless MW, Greene CM, Mulgrew A, Taggart CC, O’Neil SJ, McElvaney NG. Activation of endoplasmic reticulum-specific stress responses associated with the conformational disease Z alpha 1-antitrypsin deficiency. Journal of Immunology 2004; 172(9): 5722-6.
4. 4. Rab A, Bartoszewski R, Jurkuvenaite A, Wakefield J, Collawn JF, Bebok Z. Endoplasmic reticulum stress and the unfolded protein response regulate genomic cystic fibrosis transmembrane conductance regulator expression. American Journal of Physiology 2007; 292(2):C756-66.
5. 5. Vidal R, Cabellora B, Couve A, Hetz C. Converging pathways in the occurrence of endoplasmic reticulum (ER) stress in Huntington’s disease. Current Molecular Medicine 2011; 11(1):1-12.
6. 6. Takahashi R, Imai Y, Hattori N, Mizuno Y. Parkin and endoplasmic reticulum stress. Annals of the New York Academy of Sicences 2003; 991:101-6.
7. 7. Hoozemans JJ, Veerhuis R, Van Haastert ES, Rozemuller JM, Baas F, Eikelenboom P, Scheper W. The unfolded protein response is activated in Alzheimer’s disease. Acta Neuropathologica 2005; 110(2):165-72.
8. 8. Wong DP, Chu JM, Hung VK, Lee DK, Cheng CH, Yung KK, Yue KK. Modulation of endoplasmic reticulum chaperone GRP78 by high glucose in hippocampus of streptozotocin-induced diabetic mice and C6 astrocytic cells. Neurochemistry International 2013; 63(6):551-60.

9. 9. Wang CY, Xie JW, Wang T, Xu Y, Cai JH, Wang X, Zhao BL, An L, Wang ZY. Hypoxia-triggered m-calpain activation evokes endoplasmic reticulum stress and neuropathogenesis in a transgenic mouse model of Alzheimer’s disease. CNS neuroscience & Therapeutics 2013; 19(10):820-33.
10. 10. Kang EB, Kwon IS, Koo JH, Kim EJ, Kim CH, Lee J, Yang CH, Lee YI, Cho IH, Cho JY. Treadmill exercise represses neuronal cell death and inflammation during Aβ-induced ER stress by regulating unfolded protein response in aged presenilin 2 mutant mice. Apoptosis 2013; 18(11):1332-47.
11. 11. Park SW, Ozcan U. Potential for therapeutic manipulation of the UPR in disease. Seminars in immunopathology 2013; 35(3):351-73.
12. 12. Aşan E, Dağdeviren A. Moleküler Histoloji Hücre. Ankara: Atlas Kitapçılık, 2012: 253.
13. 13. Chaudhari N, Talwar P, Parimisetty A, Lefebvre d’Hellencourt C, Ravanan P. A molecular web: Endoplasmic reticulum stress, inflammation, and oxidative stress. Frontiers in Cellular Neuroscience 2014; 8:213.
14. 14. Buck TM, Wright CM, Brodsky JL. The activities and function of molecular chaperones in the endoplasmic reticulum. Seminars in Cell & Developmental Biology 2007; 18(6):751-61.
15. 15. Braakman I, Bulleid NJ. Protein folding and modification in the mammalian endoplasmic reticulum. Annual Review of Biochemistry 2011; 80:71-99.
16. 16. Koch GL. The endoplasmic reticulum and calcium storage. Bioessays 1990; 12(11):527-31.
17. 17. Hicke L, Schekman R. Molecular machinery required for protein transport from the endoplasmic reticulum to the Golgi complex. Bioessays 1990; 12(6):253-8.
18. 18. Malhotra JD, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress: A vicious cycle or a doubleedged sword? Antioxidants & Redox Signalling 2007; 9(12):2277-93.
19. 19. Schönthal AH. Endoplasmic reticulum stress: its role in disease and novel prospects for therapy. Scientifica (Cairo) 2012; 2012:857516.
20. 20. Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nature Cell Biology 2011; 13(3):184-90.
21. 21. Moreno JA, Halliday M, Molloy C, Radford H, Verity N, Axten JM, Ortori CA, Willis AE, Fischer PM, Barrett DA, Mallucci GR. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Science Translational Medicine 2013; 5(206):206ra138.
22. 22. Vidal RL, Figueroa A, Court FA, Thielen P, Molina C, Wirth C, Cabellora B, Kiffin R, Segura-Aguilar J, Cuervo AM, Glimcher LH, Hetz C. Targeting the UPR transcription factor XBP1 protects against Huntington's disease through the regulation of FoxO1 and autophagy. Hum Mol Genet 2012; 21(10):2245-62.
23. 23. Schroder M, Kaufman RJ. The mammalian unfolded protein response. Annual Review of Biochemistry 2005; 74:739-89.
24. 24. Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D. Perk is essential for translational regulation and cell survival during the unfolded protein response. Molecular Cell 2000; 5(5):897-904.
25. 25. Szegezdi E, Logue SE, Gorman AM, Samali A. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Reports 2006; 7(9):880-5.
26. 26. Brush MH, Weiser DC, Shenolikar S. Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1 alpha to the endoplasmic reticulum and promotes dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2. Molecular and Cellular Biology 2003; 23(4):1292-303.
27. 27. Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes & Development 1999; 13(1):76-86.
28. 28. Liu CY, Wong HN, Schauerte JA, Kaufman RJ. The protein kinase/endoribonuclease IRE1alpha that signals the unfolded protein response has a luminal N-terminal ligand-independent dimerization domain. Journal of Biological Chemistry 2002; 277(21):18346-56.
29. 29. Tirosh B, Iwakoshi NN, Glimcher LH, Ploegh HL. Rapid turnover of unspliced Xbp-1 as a factor that modulates the unfolded protein response. Journal of Biological Chemistry 2006; 281(9):5852-60.
30. 30. Thuerauf DJ, Marcinko M, Belmont PJ, Glembotski CC. Effects of the isoform-specific characteristics of ATF6 alpha and ATF6 beta on endoplasmic reticulum stress response gene expression and cell viability. Journal of Biological Chemistry 2007; 282(31):22865-78.
31. 31. Shen J, Chen X, Hendershot L, Prywes R. ER stress regulation of ATF6 localization by dissociation of BiP/ GRP78 binding and unmasking of Golgi localization signals. Developmental Cell 2002; 3(1):99-111.
32. 32. Kaufman RJ. Orchestrating the unfolded protein response in health and disease. Journal of Clinical Investigation 2002; 110(10):1389-98.
33. 33. Kadowaki H, Nishitoh H. Signaling pathways from the endoplasmic reticulum and their roles in disease. Genes (Basel) 2013; 4(3):306-33.
34. 34. McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Molecular and Cellular Biology 2001; 21(4):1249-59.
35. 35. Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K, Hori S, Kakizuka A, Ichijo H. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes & Development 2002; 16(11):1345-55.
36. 36. Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J. Caspase-12 mediates endoplasmic-reticulumspecific apoptosis and cytotoxicity by amyloid-beta. Nature 2000; 403(6765): 98-103.
37. 37. Rao RV, Hermel E, Castro-Obregon S, del Rio G, Ellerby HM, Bredesen DE. Coupling endoplasmic reticulum stress to the cell death program. Mechanism of caspase activation. Journal of Biological Chemistry 2001; 276(36):33869-74.
38. 38. Yoneda T, Imaizumi K, Oono K, Yui D, Gomi F, Katayama T, Tohyama M. Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. Journal of Biological Chemistry 2001; 276(17):13935-40.
39. 39. Szegezdi E, Fitzgerald U, Samali A. Caspase-12 and ERstress-mediated apoptosis: The story so far. Annals of the New York Academy of Sciences 2003; 1010:186-94.
40. 40. Morishima N, Nakanishi K, Takenouchi H, Shibata T, Yasuhiko Y. An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome c-independent activation of caspase-9 by caspase-12. Journal of Biological Chemistry 2002; 277(37):34287-94.
41. 41. Torres M, Matamala JM, Duran-Aniotz C, Cornejo VH, Foley A, Hetz C. ER stress signaling and neurodegeneration: At the intersection between Alzheimer’s disease and Prion-related disorders. Virus Research 2015; 207:69-75.
42. 42. Smith WW, Jiang H, Pei Z, Tanaka Y, Morita H, Sawa A, Dawson VL, Dawson TM, Ross CA. Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant alpha-synuclein-induced toxicity. Human Molecular Genetics 2005; 14(24):3801-11.
43. 43. Silva RM, Ries V, Oo TF, Yarygina O, Jackson-Lewis V, Ryu EJ, Lu PD, Marciniak SJ, Ron D, Przedborski S, Kholodilov N, Greene LA, Burke RE. CHOP/ GADD153 is a mediator of apoptotic death in substantia nigra dopamine neurons in an in vivo neurotoxin model of parkinsonism. Journal of Neurochemistry 2005; 95(4):974-86.
44. 44. Placido AI, Pereira CM, Duarte AI, Candeias E, Correia SC, Carvalho C, Cardosa S, Oliveira CR, Moreira PI. Modulation of endoplasmic reticulum stress: an opportunity to prevent neurodegeneration? CNS & Neurological Disorders Drug Targets 2015; 14(4):518-33.
45. 45. Katayama T, Imaizumi K, Manabe T, Hitomi J, Kudo T, Tohyama M. Induction of neuronal death by ER stress in Alzheimer’s disease. Journal of Chemical Neuroanatomy 2004; 28(1-2):67-78.
46. 46. Hardy J, Selkoe DJ, The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science 2002; 297(5580):353-6.
47. 47. Hartmann T, Bieger SC, Brühl B, Tienari PJ, Ida N, Allsop D, Roberts GW, Masters CL, Dotti CG, Unsicker K, Beyreuther K. Distinct sites of intracellular production for Alzheimer’s disease A beta40/42 amyloid peptides. Nature Medicine 1997; 3(9):1016-20.
48. 48. Wiey JC, Pettan-Brewer C, Ladiges WC. Phenylbutyric acid reduces amyloid plaques and rescues cognitive behavior in AD transgenic mice. Aging Cell 2011; 10(3):418-28.
49. 49. Ramalho RM, Borralho PM, Castro RE, Sola S, Steer CJ, Rodrigues CM. Tauroursodeoxycholic acid modulates p53-mediated apoptosis in Alzheimer’s disease mutant neuroblastoma cells. Journal of Neurochemistry 2002; 98(5):1610-8.
50. 50. Cortez L, Sim V. The therapeutic potential of chemical chaperones in protein folding diseases. Prion 2014; 8(2):197-202.
51. 51. Turturici G, Sconzo G, Geraci F. Hsp70 and its molecular role in nervous system diseases. Biochemistry Research International 2011; 2011:618127.
52. 52. Uversky VN, Li J, Fink AL. Trimethylamine-N-oxideinduced folding of alpha-synuclein. FEBS Letters 2001; 509(1):31-5.
53. 53. Yang DS, Yip CM, Huang TH, Chakrabartty A, Fraser PE. Manipulating the amyloid-beta aggregation pathway with chemical chaperones. Journal of Biological Chemistry 1999; 274(46):32970-4.
54. 54. Ricobaraza A, Cuadrado-Tejedor M, Garcia-Osta A. Long-term phenylbutyrate administration prevents memory deficits in Tg2576 mice by decreasing Abeta. Frontiers in Bioscience (Elite edition) 2011; 3:1375-84.
55. 55. Keene CD, Rodrigues CM, Eich T, Chhabra MS, Steer CJ, Low WC. Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington’s disease. Proceedings of the National Academy of Sciences of the United States of America 2002; 99(16):10671-6.
56. 56. Vang S, Longley K, Steer CJ, Low WC. The unexpected uses of urso- and Tauroursodeoxycholic acid in the treatment of non-liver diseases. Global Advances in Health and Medicine: Improving Healthcare Outcomes Worldwide 2014; 3(3):58-69.
57. 57. http://www.bio.utexas.edu/faculty/sjasper/bio212/ proteins.html.