Base excision repair (BER) is a DNA repair pathway known to play an important role in removing DNA damage resulting from oxidative stress. DNA repair efficiency decreases with age, and oxidative DNA damage is associated with aging and neurodegenerative diseases such as Alzheimer's disease. Alzheimer's disease (AD) pathology primarily consists of extracellular amyloid-beta plaques and neurofibrillary tangles of hyperphosphorylated tau protein. The aim of this work is to characterize the effects of defective base excision repair on tau pathology in C. elegans, in order to test the hypothesis that defects in BER can be a disease modifier of AD. Defective base excision repair has been previously studied in C. elegans using the uracil DNA glycosylase deletion mutant
ung-1. For tau pathology, the strains BR5270 (pan-neuronal over-expression of the F3 pro aggregation fragment of human Tau protein) with BR5271 (pan-neuronal over-expression of F3 pro-aggregation fragment of human Tau with mutations that abrogate aggregation) as a control have been previously used. To study the effect of defective base excision repair on tau pathology in C. elegans, the
ung-1 strain was crossed with pro- and anti- aggregate tau strains to generate tau strains with defective base excision repair. The effects of defective base excision repair on tau pathology in these strains were characterized using chemotaxis assay for memory, TMRE staining for mitochondrial function, pharyngeal pumping for nervous system function, and lifespan. Preliminary results suggest that deletion of the
ung-1 gene may exacerbate memory (3 biological replicates) and pharyngeal pumping (12 tech replicates, 4 biological replicates) in the pro-aggregate tau strain of C. elegans. The pro-aggregate tau strain with
ung-1 deletion showed significantly reduced TMRE uptake compared to
ung-1 strain. Preliminary lifespan data has not shown a decreased lifespan for pro-aggregate tau +
ung-1 compared to pro-aggregate tau alone. These results provide insight into how defective base excision repair may affect tau pathology in C. elegans. Future experiments will delve deeper into the mechanisms of these effects, with the goal of better understanding BER as a disease modifier of AD.