Lizozomal Depo Hastalığı Olan Gaucher Hastalığında Otofaji Mekanizmasının Moleküler Düzeyde İncelenmesi

Abstract

Lysosomes are the most important degradation organelles of the cell. The functions of the lysosomes depend upon the harmonious coordination between the lysosomal hydrolases and the lysosomal membrane proteins existing in the membrane around the lysosome. It is found that mutations that occur within the protein coding region of genes disrupt lysosome function, cause accumulation of substrates in the cell, and LSD. The lysosomal degradation occurs in autopaghy, the basic cellular degradation mechanism. Substrate accumulation in lysosomes, dysfunction of lysosome and autophagosome fusion, and blocking of autophagic flux are the factors of LSD. Gaucher?s disease is a LSD that occurs due to accumulation of glucosylceramid and other glycolipids in the cell as a result of mutation occurring in lysosomal membrane glycoprotein glycocerebrosidase gene, or mutation of the cofactor of this enzyme Sapozin C. In six Gaucher patients which show different genotypic features, Beklin-1, which plays role in nuckeation stage of autophagic vesicules, and ATG3, ATG5, ATG12, ATG4C, LC3, GABARAP, functional in elongation and closure of vesicules; gene expressions are analyzed in non-starvation and starvation conditions by using quantitative RT-PCR. At the control fibroblast cells, examined autophagy gene expressions increased more than starvation conditions. In non-starvation conditions quantitative analysis results showed autophagy pathway has changed in Gaucher patients. Especially ATG4C and ATG5 gene expression decreased in all patients. Correlation matrix of PCA obtained from the GAPDH gene expression compared with the Beclin-1, ATG5, ATG3 and ATG4C variations in genes have been identified to be associated with each other. This results shows high correlation between with autophagic vesicles nucleation and membrane isolation elongation phases of the genes involved in the statements. It is thought that lipid conjugation stage of autophagy mechanism is inhibited in Gaucher patients.