Reduction of RAD23A extends lifespan and mitigates pathology in a mouse model of TDP-43 proteinopathy.

ABSTRACT: 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 the TAR4 mouse model of TDP-43 pathology that genetic or antisense oligonucleotide (ASO)-mediated reduction of rad23a confers benefits on survival and behavior, histological hallmarks of disease and reduction

SUBMITTER: Guo X 

PROVIDER: S-EPMC12921049 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature