TDP-43 localizes in mRNA transcription and processing sites in mammalian neurons

Casafont, Íñigo; Bengoechea, Rocío; Tapia, Olga; Berciano, Marı́a T.; Lafarga, Miguel

doi:10.1016/j.jsb.2009.06.006

Cited by 69 publications

(53 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The majority of the TDP-43-associating proteins are hnRNP family proteins, indicating that TDP-43 is an integral part of hnRNP complexes, which associate with nascent transcripts and influence their fate (46). The biochemical findings are consistent with TDP-43's role in RNA transcription and processing and complement a recent ultrastructural study showing that TDP-43 is enriched in perichromatin fibrils, nuclear sites of transcription, and cotranscriptional splicing (47). Beside hnRNPs, several additional RNA-binding proteins were identified within TDP-43 complexes, including RBM9 (or FOX2) and CUG-BP1 (Fig.…”

Section: Discussionsupporting

confidence: 81%

ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS

Ling

Albuquerque²,

Han

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

401

382

View full text Add to dashboard Cite

Dominant mutations in two functionally related DNA/RNA-binding proteins, trans-activating response region (TAR) DNA-binding protein with a molecular mass of 43 KDa (TDP-43) and fused in sarcoma/ translocation in liposarcoma (FUS/TLS), cause an inherited form of ALS that is accompanied by nuclear and cytoplasmic aggregates containing TDP-43 or FUS/TLS. Using isogenic cell lines expressing wild-type or ALS-linked TDP-43 mutants and fibroblasts from a human patient, pulse-chase radiolabeling of newly synthesized proteins is used to determine, surprisingly, that ALS-linked TDP-43 mutant polypeptides are more stable than wild-type TDP-43. Tandem-affinity purification and quantitative mass spectrometry are used to identify TDP-43 complexes not only with heterogeneous nuclear ribonucleoproteins family proteins, as expected, but also with components of Drosha microprocessor complexes, consistent with roles for TDP-43 in both mRNA processing and microRNA biogenesis. A fraction of TDP-43 is shown to be complexed with FUS/TLS, an interaction substantially enhanced by TDP-43 mutants. Taken together, abnormal stability of mutant TDP-43 and its enhanced binding to normal FUS/TLS imply a convergence of pathogenic pathways from mutant TDP-43 and FUS/TLS in ALS.mass spectrometry | protein stability | amyotrophic lateral sclerosis | microRNA | ribonucleoproteins

show abstract

Section: Discussionsupporting

confidence: 81%

ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS

Ling

Albuquerque²,

Han

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

401

382

View full text Add to dashboard Cite

show abstract

“…All of the proteins we have shown to co-localize with RNA foci, many of the binding partners identified in our RNA pulldown, and a number of the proteins implicated in genetic variants of ALS including TARDBP, EWSR1, FUS, HNRNPA1 and HNRNPA2B1, have been localized to nuclear speckles (Zhou et al , 2000; Saitoh et al , 2004; Casafont et al , 2009). Other neuromuscular diseases have been associated with depletion of normal components of nuclear speckles including myotonic dystrophy type 1 (Smith et al , 2007; Bengoechea et al , 2012).…”

Section: Discussionmentioning

confidence: 78%

Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions

Cooper‐Knock

Walsh

Higginbottom

et al. 2014

Brain

267

348

View full text Add to dashboard Cite

show abstract

“…TDP43 localizes to sites of transcription and splicing and is postulated to be part of the spliceosome [321], while it is absent from areas of silent heterochromatin [322]. TDP43 contains two RNA recognition motifs (RRM) and shows clear preference in binding to at least five UG repeats.…”

Section: Late-onset Neurodegenerationmentioning

confidence: 99%

Unraveling the Pathways to Neuronal Homeostasis and Disease: Mechanistic Insights into the Role of RNA-Binding Proteins and Associated Factors

Ravanidis

Kattan

Doxakis

2018

IJMS

View full text Add to dashboard Cite

The timing, dosage and location of gene expression are fundamental determinants of brain architectural complexity. In neurons, this is, primarily, achieved by specific sets of trans-acting RNA-binding proteins (RBPs) and their associated factors that bind to specific cis elements throughout the RNA sequence to regulate splicing, polyadenylation, stability, transport and localized translation at both axons and dendrites. Not surprisingly, misregulation of RBP expression or disruption of its function due to mutations or sequestration into nuclear or cytoplasmic inclusions have been linked to the pathogenesis of several neuropsychiatric and neurodegenerative disorders such as fragile-X syndrome, autism spectrum disorders, spinal muscular atrophy, amyotrophic lateral sclerosis and frontotemporal dementia. This review discusses the roles of Pumilio, Staufen, IGF2BP, FMRP, Sam68, CPEB, NOVA, ELAVL, SMN, TDP43, FUS, TAF15, and TIA1/TIAR in RNA metabolism by analyzing their specific molecular and cellular function, the neurological symptoms associated with their perturbation, and their axodendritic transport/localization along with their target mRNAs as part of larger macromolecular complexes termed ribonucleoprotein (RNP) granules.

show abstract

TDP-43 localizes in mRNA transcription and processing sites in mammalian neurons

Cited by 69 publications

References 44 publications

ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS

ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS

Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions

Unraveling the Pathways to Neuronal Homeostasis and Disease: Mechanistic Insights into the Role of RNA-Binding Proteins and Associated Factors

Contact Info

Product

Resources

About