TDP-43 and FUS RNA-binding Proteins Bind Distinct Sets of Cytoplasmic Messenger RNAs and Differently Regulate Their Post-transcriptional Fate in Motoneuron-like Cells

Colombrita, Claudia; Onesto, Elisa; Megiorni, Francesca; Pizzuti, Antonio; Baralle, Francisco E.; Buratti, Emanuele; Silani, Vincenzo; Ratti, Antonia

doi:10.1074/jbc.m111.333450

Cited by 254 publications

(270 citation statements)

References 66 publications

(71 reference statements)

Supporting

Mentioning

255

Contrasting

Order By: Relevance

“…16 Several global scale analyses based on RIP-seq and CLIP-seq have been performed to identified TDP-43 mRNA targets in neuronal, non-neuronal cells, mouse brain, healthy and diseased human brain tissues. [8][9][10][11]30 These studies showed that the most significantly enriched pentamer-binding sites were GUGUG and UGUGU, confirming previous in vitro data. 7,37 Add2 brain specific PAS DSE contains 4 GU repeats in its sequence (Fig.…”

Section: Discussionsupporting

confidence: 88%

“…[29][30][31] The observation that the TDP-43 modulation of Add2 expression levels was detected in both the endogenous transcript and minigene derived mRNAs, which contains only the PAS and their respective 3 0 UTR flanking regions of Add2, and in minigene constructs in which the Add2 DSE was replaced by DSE sequences that do not contain GU repeats (Fig. 4A), further supported the possibility that TDP-43 could influence Add2 mRNA half-life through the binding to the 3 0 UTR.…”

Section: Downregulation Of Tdp-43 Results In a Reduction Of Add2 Mrnamentioning

confidence: 99%

“…TDP-43 was initially discovered as a regulator of HIV transcription 33 but since then it was implicated in multiple nuclear and cytoplasmic functions ranging from alternative splicing, 7,34 miRNA biogenesis, 35 mRNA translation, 36 mRNA stability, 30,31 to TDP-43 mRNA levels autoregulation, 16,29 Recently, it was demonstrated its involvement in 3 0 end processing of its own pre-mRNA. High levels of TDP-43 block the recognition of the first PAS present on its transcript by competing with the polyadenylation factor CstF-64 for DSE binding.…”

Section: Discussionmentioning

confidence: 99%

“…Strong et al suggested that TDP-43 stabilized the hNFL (human low molecular weight neurofilament) mRNA while an opposite destabilizing effect was observed on Vegf (vascular endothelial growth factor) and Grn (progranulin) transcripts. 30,31 In both cases TDP-43 acts by a direct interaction with a (UG) n motif or (UG)/(UGUG) motifs in stem loop structures located in their 3 0 UTR. 30,40 It was also demonstrated that TDP-43 is able to regulate the half-life of its own mRNA: in fact, overexpression of the protein promotes instability of its transcript.…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

TDP-43 regulatesβ-adducin(Add2) transcript stability

et al. 2014

View full text Add to dashboard Cite

Keywords: Add2, DSE, mRNA stability, TDP-43, 3 0 end processing, 3 0 UTR Abbreviations: RBP, RNA binding protein, DSE, downstream element, PAS, polyadenylation site, ActD, actinomycin D.TDP-43 is an RNA-binding protein involved in several steps of mRNA metabolism including transcription, splicing and stability. It is also involved in ALS and FTD, neurodegenerative diseases characterized by TDP-43 nuclear depletion. We previously identified TDP-43 as a binder of the downstream element (DSE) of the b-Adducin (Add2) brain-specific polyadenylation site (A4 PAS), suggesting its involvement in pre-mRNA 3 0 end processing. Here, by using chimeric minigenes, we showed that TDP-43 depletion in HeLa and HEK293 cells resulted in down-regulation of both the chimeric and endogenous Add2 transcripts. Despite having confirmed TDP-43-DSE in vitro interaction, we demonstrated that the in vivo effect was not mediated by the TDP-43-DSE interaction. In fact, substitution of the Add2 DSE with viral E-SV40 and L-SV40 DSEs, which are not TDP-43 targets, still resulted in decreased Add2 mRNA levels after TDP-43 downregulation. In addition, we failed to show interaction between TDP-43 and key polyadenylation factors, such as CstF-64 and CPSF160 and excluded TDP-43 involvement in pre-mRNA cleavage and regulation of polyA tail length. These evidences allowed us to exclude the pre-hypothesized role of TDP43 in modulating 3 0 end processing of Add2 pre-mRNA. Finally, we showed that TDP-43 regulates Add2 gene expression levels by increasing Add2 mRNA stability. Considering that Add2 in brain participates in synapse assembly, synaptic plasticity and their stability, and its genetic inactivation in mice leads to LTP, LTD, learning and motor-coordination deficits, we hypothesize that a possible loss of Add2 function by TDP-43 depletion may contribute to ALS and FTD disease states.

show abstract

Section: Discussionsupporting

confidence: 88%

Section: Downregulation Of Tdp-43 Results In a Reduction Of Add2 Mrnamentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

TDP-43 regulatesβ-adducin(Add2) transcript stability

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Still, genes displaying overlapping patterns of dysregulation represented only a small fraction of the total, with the majority of differentially expressed genes being distinct in each case [36]. In addition, targeted reduction in TDP43 or FUS produced disparate effects in NSC34 mouse motor neuron-like cells [62]. In an animal model of ALS, the overexpression of FUS bearing an ALS-associated mutation (R521C) significantly affected the expression of >700 genes [63].…”

Section: Rna Expressionmentioning

confidence: 99%

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

Barmada

2015

Neurotherapeutics

View full text Add to dashboard Cite

The degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) inevitably causes paralysis and death within a matter of years. Mounting genetic and functional evidence suggest that abnormalities in RNA processing and metabolism underlie motor neuron loss in sporadic and familial ALS. Abnormal localization and aggregation of essential RNA-binding proteins are fundamental pathological features of sporadic ALS, and mutations in genes encoding RNA processing enzymes cause familial disease. Also, expansion mutations occurring in the noncoding region of C9orf72-the most common cause of inherited ALS-result in nuclear RNA foci, underscoring the link between abnormal RNA metabolism and neurodegeneration in ALS. This review summarizes the current understanding of RNA dysfunction in ALS, and builds upon this knowledge base to identify converging mechanisms of neurodegeneration in ALS. Potential targets for therapy development are highlighted, with particular emphasis on early and conserved pathways that lead to motor neuron loss in ALS.

show abstract

TDP‐43 and FUS en route from the nucleus to the cytoplasm

Ederle¹,

2017

View full text Add to dashboard Cite

Misfolded or mislocalized RNA‐binding proteins (RBPs) and, consequently, altered mRNA processing, can cause neuronal dysfunction, eventually leading to neurodegeneration. Two prominent examples are the RBPs TAR DNA‐binding protein of 43 kDa (TDP‐43) and fused in sarcoma (FUS), which form pathological messenger ribonucleoprotein aggregates in patients suffering from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating neurodegenerative disorders. Here, we review the multiple functions of TDP‐43 and FUS in mRNA processing, both in the nucleus and in the cytoplasm. We discuss how TDP‐43 and FUS may exit the nucleus and how defects in both nuclear and cytosolic mRNA processing events, and possibly nuclear export defects, may contribute to neurodegeneration and ALS/FTD pathogenesis.

show abstract

TDP-43 and FUS RNA-binding Proteins Bind Distinct Sets of Cytoplasmic Messenger RNAs and Differently Regulate Their Post-transcriptional Fate in Motoneuron-like Cells

Cited by 254 publications

References 66 publications

TDP-43 regulatesβ-adducin(Add2) transcript stability

TDP-43 regulatesβ-adducin(Add2) transcript stability

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

TDP‐43 and FUS en route from the nucleus to the cytoplasm

Contact Info

Product

Resources

About