UC San Diego

As cells age they develop distinctive characteristics that are highly associated with diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). One of those highly associated characteristics is the formation of toxic protein aggregates like transactive response DNA binding protein (TDP43) that lead to disease pathology. To study the effects of TDP43 expression in aging cells we used growth assays, which showed that increased TDP43 expression is toxic to yeast cells. Our microscopy of aging cells expressing TDP43 also revealed that as cells age TDP43 expression becomes toxic, and nuclear expression seems to decrease as TDP43 expression moves to the cytoplasm and forms pathological aggregates. Due to the many important roles of TDP43 in the nucleus in its stable form, we hypothesized that in young cells low TDP43 expression wouldn’t be toxic but would become toxic as the cells aged. We found that at low expression levels of TDP43 we were able to maximize the amount of time at which we could image the aging cells before they died from the toxicity. This poses a possible mechanism by which we can observe important TDP43 expression characteristics for the entirety of the cell’s lifespan.