Nörodejeneratif Hastalıklarda Katlanmamış Protein Cevabının Tedavi Edici Potansiyeli

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

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,

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