The Mito Foundation PhD Scholarship

 

Scholar

Paula Woodbridge – commenced February 2010 –
graduated April 2015

University

University of Sydney

Supervisors

Prof Carolyn Sue

Research Institution

Kolling Institute

Project Name

Investigation of the pathogenic effects of mutations in the polymerase gamma gene

Project Overview

All forms of life depend on the ability of DNA to reproduce. Through DNA replication, an organism passes its genetic code to new cells and future generations. The molecule that actually reproduces the DNA is an enzyme called polymerase. Every living thing, from the smallest bacterium to the largest baleen whale, contains at least one DNA polymerase. The polymerase works inside our cells, where it reads our existing DNA and then synthesises a dual-stranded copy, constructing it piece by piece from the four basic DNA building blocks (called nucleotides) available in the cell.

Our mitochondria have their own DNA and a specialised polymerase to copy it. When defects in the mitochondrial polymerase occur, the mitochondria may begin to make mistakes when copying its DNA. With funding from the Mito Foundation, Paula Woodbridge successfully completed a PhD to research defects in mitochondrial Polymerase Gamma (POLG).  POLG mutations are one of the most common causes of inherited mitochondrial disease. POLG mutations prevent the polymerase from being able to select the correct nucleotides and proofread the new DNA strand, which leads to defects in the mitochondrial genome. This may result in impairment of the machinery that creates ATP (the cell’s most important form of energy). Lack of ATP can lead to defective cellular function, and even cell death. There are many neurological and muscular disorders arising from POLG mutations, and they all fall into the realm of mitochondrial disease.

Before Paula’s research, the prevalence of POLG mutations in Australian patients presenting symptoms suggestive of POLG was relatively unknown. She was able to estimate this rate with much greater certainty. She also conducted laboratory research on patient cells to learn about the mechanism of POLG defects. Taking advantage of recent advances in cell engineering, Paula cultured specialised neuron cells, growing olfactory neurospheres (ONS) and inducible pluripotent stem cells (iPS). She then identified the differences between healthy cells and POLG diseased cells. She discovered that POLG cells showed an increase in damaging superoxide production, and a decrease in the amount of mtDNA when compared with normal cells. These changes coincided with impaired cellular functioning. Her work has helped clarify the disease mechanism of POLG mutations, and may lead to the discovery of new compounds that could be used to treat POLG mutations. After successful completion of her PhD, Paula took a position at AusDiagnostics where she works to bring new diagnostic products to the Australian and European markets.

To view Paula’s final report on her research, click here.

To view Paula’s final thesis, click here.