Amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) represent a spectrum of neurodegenerative disorders characterized by the progressive loss of motor neurons seen in amyotrophic lateral sclerosis (ALS) and the cognitive and behavioral impairments caused by frontal and temporal lobe degeneration seen in frontotemporal dementia (FTD). ALS primarily affects motor function, leading to muscle weakness, atrophy, and eventual paralysis, while FTD is associated with changes in personality, executive dysfunction, and language deficits.
In addition to ALS and FTD sharing overlapping genetic, molecular, and pathological features, 50% of ALS patients experience clinical symptoms resembling FTD and 30% of FTD patients experience motor dysfunction. The presence of a repeat expansion mutation in the C9orf72 gene is the most common genetic cause of both these diseases. Most patients that present with ALS-FTD with the C9ORF72 mutation will also have pathology associated with TDP-43, a protein encoded by the TARDBP gene. TDP-43 has been shown to translocate from the nucleus into the cytoplasm where it is known to form toxic insoluble, hyperphosphorylated aggregates. Although much focus has been on understanding the effects of the TDP-43 proteinopathy in motor neurons, this project aims to characterize the loss of TDP-43 in a human microglial cell line (HMC3) via siRNA knockdown. Here we show that knockdown of TDP-43 incites activation of TBK1 independent of NFkB signaling in HMC3 cells. Revealing the consequences of loss of TDP-43 in microglia may provide a better functional and mechanistic understanding of ALS-FTD that can lead to novel biomarkers and therapeutic targets.