Anna Konopka
Understanding the causes of DNA damage in dementia associated with abnormal TDP-43
Award
Dementia Australia Research Foundation Project Grant
Status
Completed
Start Date
9 April 2023
About the project
DNA carries genes that define any living being. The genes are essential for function of the whole organism, but they are damaged every day due to normal cellular processes and exposition to toxic agents. Therefore, efficient DNA repair mechanisms are crucial for the proper functioning of genes and the maintenance of healthy cells. Abnormal accumulation of DNA damage actively contributes to neurodegeneration in Alzheimer’s disease and frontotemporal lobar degeneration (FTLD), the two most common causes of dementia.
However, precise mechanisms underlining this phenomenon are unknown. In both, Alzheimer’s disease and frontotemporal lobar degeneration, an abnormal protein called TDP-43 is present. Interestingly, it was recently discovered that TDP-43 repairs DNA. Given that DNA is damaged in dementia and TDP-43 does not work properly, defective DNA repair may be a potential cause of the disease. DNA is packed within the small nucleus of a cell, and to prevent issues arising from the intertwined nature of DNA, specialised proteins called topoisomerases cut the DNA. The sites of these cleavages are not random and have a significant impact on critical cellular functions.
In this project, Dr Anna Konopka discovered that the TDP-43 protein, which is abnormal in dementia, disrupts the function of topoisomerase 2 beta, leading to DNA damage. This research has led to the identification of the exact sites of DNA breaks in neurons expressing dementia-associated TDP-43 protein. This study holds great potential to uncover the hidden causes of dementia, potentially paving the way for the development of effective treatments in the future.
Where are they now?
At the time of this award, Dr Anna Konopka was a postdoctoral researcher at Macquarie University in Sydney.
