TDP-43 functions within a network of hnRNP proteins to inhibit the production of a truncated human SORT1 receptor

Mohagheghi, Fatemeh; Prudencio, Mercedes; Stuani, Cristiana; Cook, Casey; Jansen-West, Karen; Dickson, Dennis W.; Petrucelli, Leonard; Buratti, Emanuele

doi:10.1093/hmg/ddv491

Cited by 76 publications

(81 citation statements)

References 51 publications

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“…The splicing of specific annotated exons has been shown to depend on the interaction of TDP-43 with multiple splicing factors [59]. We hypothesised that some cryptic exons may be included indirectly through a loss of TDP-43’s interactions with different RBPs.…”

Section: Resultsmentioning

confidence: 99%

Quantitative analysis of cryptic splicing associated with TDP-43 depletion

Humphrey

Emmett

Fratta³

et al. 2017

BMC Med Genomics

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BackgroundReliable exon recognition is key to the splicing of pre-mRNAs into mature mRNAs. TDP-43 is an RNA-binding protein whose nuclear loss and cytoplasmic aggregation are a hallmark pathology in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). TDP-43 depletion causes the aberrant inclusion of cryptic exons into a range of transcripts, but their extent, relevance to disease pathogenesis and whether they are caused by other RNA-binding proteins implicated in ALS/FTD are unknown.MethodsWe developed an analysis pipeline to discover and quantify cryptic exon inclusion and applied it to publicly available human and murine RNA-sequencing data.ResultsWe detected widespread cryptic splicing in TDP-43 depletion datasets but almost none in another ALS/FTD-linked protein FUS. Sequence motif and iCLIP analysis of cryptic exons demonstrated that they are bound by TDP-43. Unlike the cryptic exons seen in hnRNP C depletion, those repressed by TDP-43 cannot be linked to transposable elements. Cryptic exons are poorly conserved and inclusion overwhelmingly leads to nonsense-mediated decay of the host transcript, with reduced transcript levels observed in differential expression analysis. RNA-protein interaction data on 73 different RNA-binding proteins showed that, in addition to TDP-43, 7 specifically bind TDP-43 linked cryptic exons. This suggests that TDP-43 competes with other splicing factors for binding to cryptic exons and can repress cryptic exon inclusion.ConclusionsOur quantitative analysis pipeline confirms the presence of cryptic exons during the depletion of TDP-43 but not FUS providing new insight into to RNA-processing dysfunction as a cause or consequence in ALS/FTD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-017-0274-1) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Quantitative analysis of cryptic splicing associated with TDP-43 depletion

Humphrey

Emmett

Fratta³

et al. 2017

BMC Med Genomics

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“…This is a possibility that will require further study. Whilst TDP‐43 binds to thousands of constitutive exons throughout the transcriptome, only 44 undergo skipping in the presence of LCDmut induced GOF; this is likely due to the cooperative nature of splicing and that TDP‐43 is only one of many factors involved in the regulation of the inclusion/exclusion of the thousands of exons it binds to (Mohagheghi et al , 2016). …”

Section: Discussionmentioning

confidence: 99%

Mice with endogenous TDP ‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis

et al. 2018

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TDP‐43 (encoded by the gene TARDBP) is an RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, how TARDBP mutations trigger pathogenesis remains unknown. Here, we use novel mouse mutants carrying point mutations in endogenous Tardbp to dissect TDP‐43 function at physiological levels both in vitro and in vivo. Interestingly, we find that mutations within the C‐terminal domain of TDP‐43 lead to a gain of splicing function. Using two different strains, we are able to separate TDP‐43 loss‐ and gain‐of‐function effects. TDP‐43 gain‐of‐function effects in these mice reveal a novel category of splicing events controlled by TDP‐43, referred to as “skiptic” exons, in which skipping of constitutive exons causes changes in gene expression. In vivo, this gain‐of‐function mutation in endogenous Tardbp causes an adult‐onset neuromuscular phenotype accompanied by motor neuron loss and neurodegenerative changes. Furthermore, we have validated the splicing gain‐of‐function and skiptic exons in ALS patient‐derived cells. Our findings provide a novel pathogenic mechanism and highlight how TDP‐43 gain of function and loss of function affect RNA processing differently, suggesting they may act at different disease stages.

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“…Altered levels or mutations in RNA binding proteins (RBPs) are associated with neurological diseases, including spinal muscular atrophy, fragile X syndrome, amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) (Mohagheghi et al, 2016) and Alzheimer’s disease (AD) (Belzil et al, 2013; Nussbacher et al, 2015; Polymenidou et al, 2012). ALS is a fatal neurodegenerative disorder characterized by progressive loss of upper and lower motor neurons.…”

Section: Introductionmentioning

confidence: 99%

Protein-RNA Networks Regulated by Normal and ALS-Associated Mutant HNRNPA2B1 in the Nervous System

Martínez

Pratt

Nostrand

et al. 2016

Neuron

144

168

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HnRNPA2B1 encodes an RNA binding protein associated with neurodegeneration. However, its function in the nervous system is unclear. Transcriptome-wide cross-linking and immunoprecipitation in mouse spinal cord discover UAGG motifs enriched within ~2,500 hnRNP A2/B1 binding sites and an unexpected role for hnRNP A2/B1 in alternative polyadenylation. HnRNP A2/B1 loss results in alternative splicing (AS), including skipping of an exon in amyotrophic lateral sclerosis (ALS)-associated D-amino acid oxidase (DAO) that reduces D-serine metabolism. ALS-associated hnRNP A2/B1 D290V mutant patient fibroblasts and motor neurons differentiated from induced pluripotent stem cells (iPSC-MNs) demonstrate abnormal splicing changes, likely due to increased nuclear-insoluble hnRNP A2/B1. Mutant iPSC-MNs display decreased survival in long-term culture, and exhibit hnRNP A2/B1 localization to cytoplasmic granules as well as exacerbated changes in gene expression and splicing upon cellular stress. Our findings provide a cellular resource and reveal RNA networks relevant to neurodegeneration, regulated by normal and mutant hnRNP A2/B1.

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TDP-43 functions within a network of hnRNP proteins to inhibit the production of a truncated human SORT1 receptor

Cited by 76 publications

References 51 publications

Quantitative analysis of cryptic splicing associated with TDP-43 depletion

Quantitative analysis of cryptic splicing associated with TDP-43 depletion

Mice with endogenous TDP ‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis

Protein-RNA Networks Regulated by Normal and ALS-Associated Mutant HNRNPA2B1 in the Nervous System

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