Abstract

Protein misfolding is inevitable, 30% of newly synthesized polypeptides can end up misfolded, and such proteins are either refolded or eliminated by cellular quality control pathways. These pathways include the ubiquitin proteosome system and autophagy. In recent years, protein misfolding has been implicated in the pathophysiology of many diseases such as diabetes, neurological disorders and cancer. Studies from our laboratory have shown that choroid plexus carcinoma tumors are characterized by the formation of aggresomes at the microtubules organizing centers (MTOC) in formalin fixed and paraffin embedded (FFPE) tumor tissues. This was further confirmed by the development of choroid plexus carcinoma cell line (CCHE-45) which was characterized by the constitutive formation of aggresomes at MTOC. Aggresome formation implies presence of toxic protein over load and/or defective autophagy. The role of autophagic flux in the removal of aggresomes was further investigated. CCHE-45 cells displayed an increase in both basal and induced autophagic flux. Furthermore, microtubule-associated protein light chain 3 A- variant 1 (LC3A-V1) expression was silenced by promoter methylation in these cells. Restoring LC3A-V1 resulted in the elimination of the aggresomes and the recruitment of Lysosomal-Associated Membrane Protein (LAMP2) independent from autophagosome formation. Based on these findings we suggest that quality control autophagy in CCHE-45 is mediated by LC3A in aggresomes clearance. We propose that perturbation in the autophagic pathway by the absence of LC3A expression leads to a failure in aggresome degradation thus overcoming misfolded protein overload.

Department

Biotechnology Program

Graduation Date

6-1-2017

Submission Date

May 2017

First Advisor

Moustafa, Ahmed

Committee Member 1

Zada, Suheir

Committee Member 2

Azzazy, Hassan

Extent

111 p.

Document Type

Doctoral Dissertation

Rights

The author retains all rights with regard to copyright. The author certifies that written permission from the owner(s) of third-party copyrighted matter included in the thesis, dissertation, paper, or record of study has been obtained. The author further certifies that IRB approval has been obtained for this thesis, or that IRB approval is not necessary for this thesis. Insofar as this thesis, dissertation, paper, or record of study is an educational record as defined in the Family Educational Rights and Privacy Act (FERPA) (20 USC 1232g), the author has granted consent to disclosure of it to anyone who requests a copy.

Institutional Review Board (IRB) Approval

Not necessary for this item

Comments

The Youssef Gameel Fellowship TWAS (The World Academy of Science), L'Oreal Women in Science Fellowship Award STDF (The Science and Technology Development Fund)

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