TDP‐43, recently identified as a signature protein of the pathogenic inclusions in the brains cells of frontotemporal lobar degeneration patients, is a 43 kDa RNA‐binding protein. It has been known mainly as a nuclear factor capable of repressing transcription and promoting exon exclusion. TDP‐43 also forms distinct nuclear substructures linking different types of nuclear bodies. In this study, we provide the first evidence supporting TDP‐43 as a neuronal activity‐responsive factor in the dendrites of hippocampal neurons. In particular, TDP‐43 resides in the somatodendrites mainly in the form of RNA granules colocalized with the post‐synaptic protein PSD‐95. These granules also contain RNAs including at least the β‐actin mRNA and CaMKIIα mRNA. Furthermore, TDP‐43 is localized in the dendritic processing (P) body and it behaves as a translational repressor in an in vitro assay. Related to this, repetitive stimuli by KCl greatly enhance the colocalization of TDP‐43 granules with FMRP and Staufen 1, two RNA‐binding proteins known to regulate mRNA transport and local translation in neurons. These data together suggest that TDP‐43 is a neuronal activity‐responsive factor functioning in the regulation of neuronal plasticity, the impairment of which would lead to the development of certain forms of neurodegenerative diseases including frontotemporal lobar degeneration.

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BackgroundThe evolution of complex sub-cellular structures such as the synapse requires the assembly of multiple proteins, each conferring added functionality to the integrated structure. Tracking the early evolution of synapses has not been possible without genomic information from the earliest branching animals. As the closest extant relatives to the Eumetazoa, Porifera (sponges) represent a pivotal group for understanding the evolution of nervous systems, because sponges lack neurons with clearly recognizable synapses, in contrast to eumetazoan animals.Methodology/Principal FindingsWe show that the genome of the demosponge Amphimedon queenslandica possesses a nearly complete set of post-synaptic protein homologs whose conserved interaction motifs suggest assembly into a complex structure. In the critical synaptic scaffold gene, dlg, residues that make hydrogen bonds and van der Waals interactions with the PDZ ligand are 100% conserved between sponge and human, as is the motif organization of the scaffolds. Expression in Amphimedon of multiple post-synaptic gene homologs in larval flask cells further supports the existence of an assembled structure. Among the few post-synaptic genes absent from Amphimedon, but present in Eumetazoa, are receptor genes including the entire ionotropic glutamate receptor family.Conclusions/SignificanceHighly conserved protein interaction motifs and co-expression in sponges of multiple proteins whose homologs interact in eumetazoan synapses indicate that a complex protein scaffold was present at the origin of animals, perhaps predating nervous systems. A relatively small number of crucial innovations to this pre-existing structure may represent the founding changes that led to a post-synaptic element.