Developing RNA Therapeutics for TDP-43 Proteinopathy in ALS/FTD.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are both fatal neurodegenerative disorders characterized by neuronal loss. ALS is primarily characterized by motor impairments stemming from degeneration of motor neurons, whereas the main symptoms of FTD include changes in personality, behavior, and language stemming from degeneration of cortical neurons in the frontal and temporal lobes. ALS and FTD exist on a clinical continuum, where some patients present with features of both diseases. A molecular hallmark shared by almost all ALS patients and approximately half of FTD patients is the pathological aggregation of the RNA-binding protein TDP-43. It has recently been established that the solubility of TDP-43 is increased by its binding to RNA. I hypothesize that aberrant aggregation of TDP-43 in ALS/FTD models is due to alterations in TDP-43:RNA interactions. I have utilized in vitroaggregation assays with purified TDP-43 and short 34 nucleotide bait RNAs designed to bind TDP-43. I find that bait RNAs can prevent aggregation of all tested disease-linked TDP-43 variants. I also find that disease-causing missense mutations in TDP-43 can alter the potency of bait RNAs against aggregation of TDP-43. These results suggest that there are differences in the RNA interactions of TDP-43 in disease. These findings also support the development of bait RNAs as a therapeutic strategy for ALS/FTD.