Synaptic changes contribute to persistent extra-motor behaviour deficits in the rNLS8 TDP-43 mouse model of amyotrophic lateral sclerosis

Extra-motor symptoms are increasingly recognised in amyotrophic lateral sclerosis (ALS), encompassing cognitive, social, and behavioural deficits that can substantially impact quality of life. TAR DNA binding protein 43 (TDP-43) pathology is the central disease marker of almost all cases of ALS and approximately half of all frontotemporal dementia (FTD). However, the mechanisms linking TDP-43 pathology with extra-motor symptoms in TDP-43-associated neurodegenerative diseases remain unresolved. In this study, we used the rNLS8 mouse model, which expresses human TDP-43 with an ablated nuclear localisation sequence (hTDP-43deltaNLS) in a doxycycline-regulatable manner causing progressive motor decline reminiscent of ALS, to delineate the molecular changes associated with disease-relevant phenotypes. These RNA-seq datasets are from the left rostral cortex of control and rNLS8 mice (n = 4/group, 2 male and 2 female) and there are two sets of data from two different experimental paradigms. 1) RNA-seq of rostral cortex after 2 weeks off doxycycline, which corresponds to an early disease timepoint in these mice. 2) RNA-seq of rostral cortex after 2 weeks off doxycycline followed by a further 6 week ON doxycycline recovery phase, whereby rNLS8 mice functionally recover from motor deficits induced by cytoplasmic TDP-43 expression.