Thesis Format
Monograph
Degree
Master of Science
Program
Anatomy and Cell Biology
Supervisor
Duennwald, Martin L.
2nd Supervisor
Choy, Wing-Yiu (James)
Co-Supervisor
Abstract
DnaJC7 is a co-chaperone implicated in a neurodegenerative disease called Amyotrophic Lateral Sclerosis (ALS). The aim of my research was to discover its role in protein homeostasis, and how DnaJC7 contributes to preventing protein homeostasis failure. To this end, we employed both a yeast and SH-SY5Y mammalian cell model to track the localization of DnaJC7, expression and its protection against toxicity. In both models, we found that DnaJC7 changes localization under conditions that increase protein misfolding within the cell. Also, under conditions of stress that illicit an increase in proteostatic stress, DnaJC7 can reduce the ensuing cellular toxicity. Several ALS-associated variants of DnaJC7 were unable to recover the toxicity, and many were significantly degraded under basal conditions compared to wild-type DnaJC7. We conclude that DnaJC7 has a protective role during protein homeostasis failure, providing a new potential therapeutic target for treating ALS disease.
Summary for Lay Audience
Each fold in a paper airplane has a purpose. Whether it is the creation of the wings or tail, the folds determine the final structure. After each flight, the plane may bend or crumple from hitting the ground. Thus, we must refold the parts that were damaged or recycle the plane to start again. In our cells, we have millions of “paper airplanes” called proteins. Each protein is slightly different, with different purposes, trajectories, and structures. But you can only imagine with millions of proteins flying around inside the cell, how chaotic it can be. Proteins are constantly moving and bumping everywhere. Just like paper airplanes, these proteins eventually lose their original folds, and their structures start to collapse.
Thankfully, in our cells, we have an amazing maintenance crew called molecular chaperones. Molecular chaperones check for broken proteins and just like our crumpled airplanes, they can either refold or dispose of them.
The mystery begins in people with the disease Amyotrophic Lateral Sclerosis (ALS). For this incurable disease that affects millions, the cause is unknown. But only recently have we detected a new prime suspect; a rogue molecular chaperone called DnaJC7. DnaJC7 is a co-chaperone, meaning it helps other chaperones to function properly. Somehow, it misbehaves in ALS patients and completely disturbs the whole repair process. Chaos ensues, like a room being slowly filled with broken paper airplanes, proteins start to accumulate, and cells eventually die from all the clutter.
We still know little about why DnaJC7 acts this way. I plan to be one of the first ones to find out what goes wrong with DnaJC7 in ALS. With the evidence I find, we will be one step closer to solving the mystery of ALS and hopefully finally finding a cure.
Recommended Citation
Kim, Young Joon, "DnaJC7 Antagonizes the Toxic Effects of Proteostasis Stress" (2025). Electronic Thesis and Dissertation Repository. 10882.
https://ir.lib.uwo.ca/etd/10882
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.