Therapeutic reduction of RAD23A extends lifespan and mitigates pathology in TDP-43 mice

Protein misfolding and aggregation are cardinal features of neurodegenerative disease (NDD) and they contribute to pathophysiology by both loss-of-function (LOF) and gain-of-function (GOF) mechanisms. This is well exemplified by TDP-43 which aggregates and mislocalizes in several NDDs. The depletion of nuclear TDP-43 leads to reduction in its normal function in RNA metabolism and the cytoplasmic accumulation of TDP-43 leads to aberrant protein homeostasis. A modifier screen found that loss of rad23 suppressed TDP-43 pathology in invertebrate and tissue culture models. Here we show in a mouse model of TDP-43 pathology that genetic or antisense oligonucleotide (ASO)-mediated reduction in the RAD23A confers benefits on survival and behavior, histological hallmarks of disease and reduction of mislocalized and aggregated TDP-43. This results in improved function of the ubiquitin-proteasome system (UPS) and correction of transcriptomic alterations evoked by pathologic TDP-43. RAD23A-dependent remodeling of the insoluble proteome appears to be the key event driving pathology in this model. As TDP-43 pathology is prevalent in both familial and sporadic NDD, targeting RAD23A may have therapeutic potential. Overall design: In order to gain insight into the mechanisms underlying RAD23A actions in a TDP-43-based mouse model of ALS/FTD (TDP-43Tg/+), we utilized antisense oligos to knock down Rad23a in the mouse motor cortex. Scrambled antisense oligos were used as a control. Both wild-type (WT) and TDP-43Tg/+ mice's motor cortex were treated with scrambled and rad23a knockdown ASOs. We used ten biological replicates for each condition. To identify genes associated with the disease, we compared WT scrambled with TDP-43Tg/+ scrambled, and to identify genes associated with the treatment, we compared TDP-43Tg/+ scrambled with TDP-43Tg/+ rad23a knockdown ASO-treated mice.