Baldacchino, T. | bioRxiv Science

bioRxiv2026

SNRNP70 interacts with TDP-43 to promote RNP granule localisation and regulate motor neuron development

SNRNP70 is a core spliceosomal protein that localises to both the nucleus and cytoplasm. Previous studies have implicated SNRNP70 in regulating axonal stability and the transport of specific mRNAs during motor neuron development in zebrafish. Although the molecular functions and protein interactions of SNRNP70 in pre-mRNA splicing are well established, the mechanisms underlying its cytoplasmic functions remain poorly understood. Here, we show that SNRNP70 and TDP-43 exhibit similar localisation patterns in developing and mature neurons and co-associate in both nuclear and non-nuclear compartments, including axonal projections. We identify a functional interaction between SNRNP70 and TDP-43 that is essential for motor neuron development and demonstrate that the recruitment of SNRNP70 to cytoplasmic ribonucleoprotein (RNP) granules depends on TDP-43. These findings identify a previously unrecognised cytoplasmic function of TDP-43 in directing SNRNP70-containing RNP granule assembly, thereby linking TDP-43 to the splicing-independent functions of SNRNP70 during motor neuron development.

neuroscience↗

bioRxiv2026

Differential TDP-43 interactomes between the cortex and cerebellum in the mouse

TAR DNA binding protein 43 (TDP-43) is the core pathogenic protein across a spectrum of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases, but its pathological deposition shows regional selectivity, with abundant TDP-43 positive aggregates in the frontal cortex and spinal cord, and a much lower burden in the cerebellum. In health, TDP-43 expression in the cerebellum is higher than in cortex, hence what underpins this differential vulnerability to TDP-43 aggregation is unclear. Here we demonstrate that in healthy C57Bl/6J mice not only is TDP-43 expression higher in the cerebellum than the cortex, but that this expression difference is driven primarily by differences in cytoplasmic load. Mass spectrometry analysis of TDP-43 pull downs from the cortex and cerebellum of healthy mice identified TDP-43 interactors across a number of core functional pathways, with numerous differences between the two brain regions. Data are available via ProteomeXchange with identifier PXD062532. Notably, there were more interactors identified in both nuclear and cytoplasmic fractions within the cortex than the cerebellum. Putative interactions with four core paraspeckle proteins; SFPQ, NONO, FUS and PSPC1 were confirmed using immunoprecipitation and western blot analysis. Follow up validation using proximity ligation assay showed abundant perinuclear cytoplasmic interactions between TDP-43 and all four paraspeckle proteins in both large motor cortex neurons and purkinje cells, with significantly reduced nuclear interactions detected in the motor cortex for SFPQ, FUS and PSPC1. These findings suggest that TDP-43-protein interactions markedly differ between the TDP-43 pathogenesis vulnerable cortex and relatively resistant cerebellum and exploring these differences may yield new insight into disease mechanisms within ALS/FTD.

neuroscience↗