MSc. Thesis Defense:Seval Kılıç
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  • MSc. Thesis Defense:Seval Kılıç

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THE ROLE OF ATYPICAL AND CLASSICAL PROTEIN KINASE C ISOZYMES IN AUTOPHAGY AND MODULATION OF LYSOSOMAL pH BY VACUOLAR ATPase AS AN ALTERNATIVE TREATMENT APPROACH FOR GAUCHER DISEASE

 

 

Seval Kılıç
BIO, MSc. Thesis, 2017

 

Thesis Jury

Assoc. Prof. Dr. Devrim Gözüaçık (Thesis Advisor), Assoc. Prof. Özlem Kutlu (Thesis Co-Advisor), Prof. Serap Dökmeci, Prof. Funda Yağcı Acar, Assist. Prof. Murat Kaya Yapıcı

 

 

Date & Time: 28th July, 2017 –  02.00 PM

Place: L055

Keywords : Protein kinase C, PKCζ, Autophagy, Gaucher disease, V-ATPase

 

Abstract

 

 

Autophagy is conserved degradation mechanism for long-lived proteins and organelle maintaining cellular homeostasis in eukaryotes. Under stress conditions increased autophagic activity acts as stress response in cells. Protein Kinase C family isozymes are Serine/Threonine kinases involved in many crucial cellular and disease related pathways. According to their activation mechanism they are categorized to three subgroups, classical (cPKC), novel (nPKC) and atypical (aPKC) PKC’s. Although PKC’s roles are identified many signal pathways, their involvement in autophagy is not very well studied. In this study, the role of atypical isozyme PKCζ and classical isozyme PKCβII on autophagy were investigated. It was shown that PKCζ is upregulating autophagy. Autophagic defects are involved in many disease mechanisms especially in lysosomal storage disorders. Gaucher disease (GD) is the most common rare genetic disorder. Mutations in GBA1 gene causes dysfunctional glucocerebrosidase enzyme resulting in lysosomal accumulation of glucosylceramide. We identified that lysosomal pH of Gaucher cells was more basic than healthy cells. In lysosomes, V-ATPase is the main proton pump to maintain acidic pH. H subunit of V-ATPase catalytic domain overexpression decreased pH, glucocerebrosidase enzyme activity increased and lipid droplets were diminished in Gaucher cells. Reacidification of lysosomes by V-ATPase-H overexpression may have a potential as an alternative therapeutic treatment for Gaucher disease.