Thesis Format

Monograph

Transferring organelles into native neurons: A disease-modifying therapy for neurodegenerative disorders

Author

Lohiny Balendran, The University of Western OntarioFollow

Degree

Master of Science

Program

Anatomy and Cell Biology

Supervisor

Rajakumar, Nagalingam

2nd Supervisor

Renaud, Stephen J

Abstract

Currently, there are no disease-modifying therapies to counter the progression of neurodegenerative diseases that are associated with mitochondrial dysfunction in the early stages. In this study, we have used a novel strategy of cell fusion to transfer mitochondria from one cell to another using fusogens (syncytin 1 and syncytin 2). Syncytins are placental proteins encoded by endogenous retroviral envelope genes that promote cellular fusion. In this study, we have proposed that donor cells engineered to stably express syncytin when cocultured with recipient cells will allow fusion and facilitate the transfer of mitochondria into recipient cells. Syncytin-mediated systems revealed about 16.6-18.5% cell fusion efficiencies in N2a and SH-SY5Y cells. The present work is proof that our strategy of engineering syncytin expression systems allows cell fusion in neurons.

Keywords: neurodegeneration, mitochondria, cell fusion, syncytins, fusion efficiency, heterologous system, engineered, progression, cocultured, mitochondrial transfer

Summary for Lay Audience

Neurodegenerative disorders are slow-progressing, profoundly depressing, and linked with poor quality of life. Environmental variables and age have a role in the course and clinical symptoms. Oxidative stress and the formation of misfolded protein aggregates are frequent and important aspects of neurodegenerative illnesses and result in mitochondrial dysfunction that often accelerates the development of neurodegenerative disorders, including AD and PD. So far, efforts to slow or stop cellular dysfunction by utilizing biologically active chemicals, tropic factors, and viral-mediated gene transfer have been mostly ineffective. Our long-term goal is to transfer mitochondria into dying neurons at an early stage of the disease, as this would slow the progression of the disease while maintaining the neuronal functionality of the damaged brain area. We proposed employing a new technique called cell fusion to introduce mitochondria (and maybe other organelles) from young neurons with the same characteristics into neurons that are experiencing organelle stress and malfunction. Cell fusion is linked to having more than one nucleus, and it is not known if cell functions are compatible, especially in neurons. If mitochondria could be moved to a host cell, it's still not clear if they would join the existing network of organelles, live for a long time, and work properly. The goal of the current study is to find out if organelles, especially mitochondria, can be fused together and transferred between neurons. We used the placental proteins syncytins that code for endogenous retroviral envelope genes which maintain fusogenic function. In this study, we wanted to determine whether neurons allow the fusion and transfer of mitochondria. We did this by using two stable neuronal cell lines and in vitro methods to keep things simple and avoid the experimental variations that emerge with an in vivo approach. Syncytin-mediated cell fusion between two different cell types showed about 18-20% of the cells were able to fuse and allow the transfer of mitochondria between the neuronal cells. The results of our research will pave the way for a new way to treat neurodegenerative diseases that will target the mechanisms that cause neuronal damage without affecting normal neuronal communication.

Recommended Citation

Balendran, Lohiny, "Transferring organelles into native neurons: A disease-modifying therapy for neurodegenerative disorders" (2023). Electronic Thesis and Dissertation Repository. 9249.
https://ir.lib.uwo.ca/etd/9249