RNA targets of TDP-43 identified by UV-CLIP are deregulated in ALS

Xiao, Shangxi; Sanelli, Teresa; Dib, Samar; Sheps, David S.; Findlater, Joseph; Bilbao, Juan M.; Keith, Julia; Zinman, Lorne; Rogaeva, Ekaterina; Robertson, Janice

doi:10.1016/j.mcn.2011.02.013

Cited by 142 publications

(133 citation statements)

References 40 publications

Supporting

Mentioning

128

Contrasting

Order By: Relevance

“…These viral DSE sequences do not contain GU repeats, the most common binding site of TDP-43. [7][8][9][10][11] In addition, the L-SV40 polyadenylation signal RNA was used as a model in a functional proteomic approach to identify the components of the pre-mRNA 3 0 end processing complex and TDP-43 was not identified among the isolated factors, 27 strongly suggesting it does not bind the viral DSE. Therefore, the mutant constructs were transfected into HeLa cells after siRNA knock-down of the endogenous TDP-43, and total RNA analyzed by Northern blot.…”

Section: Down-regulation Of Tdp-43 Results In a Reduction Of Add2 Mrnmentioning

confidence: 99%

“…[4][5][6] It mainly recognizes in its target transcripts GU/UG repeat motifs preferentially localized in long intronic regions, splice sites and 3 0 UTRs. [7][8][9][10][11] TDP-43 has recently been associated with neurodegenerative diseases, such as amyotrophic lateral sclerosis (also called Luo-Ghering disease) and frontotemporal lobular dementia (ALS and FTLD, respectively). 12 In these diseases TDP-43 is found as the major component of pathological cytoplasmic inclusions.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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: Down-regulation Of Tdp-43 Results In a Reduction Of Add2 Mrnmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TDP-43 regulatesβ-adducin(Add2) transcript stability

et al. 2014

View full text Add to dashboard Cite

show abstract

“…TDP43 binds to and regulates thousands of RNA targets [13,14,[36][37][38], and is thus in a unique position to dramatically affect gene expression on a global scale. The RNA-binding domains of TDP43 and FUS are essential for toxicity in ALS model systems, testifying to the importance of RNA dysregulation in ALS pathogenesis [34,[39][40][41].…”

Section: Rna Expressionmentioning

confidence: 99%

“…The RNA-binding domains of TDP43 and FUS are essential for toxicity in ALS model systems, testifying to the importance of RNA dysregulation in ALS pathogenesis [34,[39][40][41]. Immunoprecipitation studies in murine brain [14], dissociated primary cortical neurons [37], and human brain [13] and cell lines [13,38] showed that TDP43 recognizes nearly one-thrid of all transcribed genes by binding to redundant GU-rich sequences [42]. While nuclear TDP43 binds preferentially to distal intronic sequences, cytoplasmic TDP43 recognizes more 3' untranslated region (UTR) binding sites [13].…”

Section: Rna Expressionmentioning

confidence: 99%

“…Several key findings link aberrant ADAR2 functioning with the development of motor neuron loss in ALS. First, downregulation of ADAR isoforms has been observed in human iPSC-derived neurons from patients with C9orf72-linked ALS [68], as well as in TDP43-deficient cell lines [38]. Second, abnormal ADARmediated RNA editing was noted in worms lacking TDP-1, the Caenorhabditis elegans ortholog of TDP43 [76].…”

Section: Rna Expressionmentioning

confidence: 99%

See 1 more Smart Citation

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

RNA targets of TDP-43 identified by UV-CLIP are deregulated in ALS

Cited by 142 publications

References 40 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