TDP‐43, the signature protein of FTLD‐U, is a neuronal activity‐responsive factor

Abstract

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.

Identification of linc-NeD125, a novel long non coding RNA that hosts miR-125b-1 and negatively controls proliferation of human neuroblastoma cells

“…Overall, the evidence that: i) TDP-43 directly interacts with the mature form of linc-NeD125, ii) such interaction takes place only in differentiation conditions, when linc-NeD125 is stabilised, and iii) TDP-43 depletion caused a drastic reduction of linc-NeD125, suggest that TDP-43 may contribute to the control of linc-NeD125 stability. This activity played by TDP-43 in RA-treated cells is in line with its role as a neuronal activity-responsive factor 53 and as a protein directly involved in neuronal differentiation. 27,54 In conclusion, we unveiled different layers of gene expression regulation that converge on the same gene locus to satisfy the demand of increased amounts of 2 ncRNAs, miR-125b-1 and linc-NeD125, during neuronal differentiation.…”

The self-interaction of native TDP-43 C terminus inhibits its degradation and contributes to early proteinopathies

“…The 293T cells were grown in Dulbecco's modified Eagle's medium, supplemented with 10% fetal bovine serum, 1% penicillin/ streptomycin and 1% l-glutamate. Primary cultures of rat hippocampal neurons were prepared from embryonic day 17 rat embryos as previously described by Wang et al 7 . All procedures for handling the rat were carried out in accordance with the guidelines approved by the Institutional Animal Care and Utilization Committee, Academia Sinica.…”

“…T he aggregation of misfolded, phosphorylated, ubiquitinated C-terminal fragments of TAR DNA-binding protein 43 (TDP-43) is a common characteristic in frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis (ALS) [1][2][3][4][5][6][7][8] . Among mammals, zebrafish and flies, the protein sequence, biochemical properties and biological functions of TDP-43 are well conserved.…”

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

“…Within the nucleus, TDP43 has essential roles in RNA transcription, splicing, and stability [13,14,[47][48][49][50], and transports select mRNA to localized sites of translation within the cytoplasm [20,51,52]. In addition to its function in RNA trafficking, cytoplasmic TDP43 also helps regulate RNA translation and homeostasis by sequestering transcripts in RNA granules [53][54][55][56].…”

“…In addition to their roles in sequestering RNAs within stress granules, TDP43 and FUS shuttle RNA from the nucleus to the dendrites in an activity-dependent process [20,51,52,104]. Disease-causing mutations in TARDBP reduce the density and mobility of these RNA particles and interfere with their transport into dendrites [20,51].…”