Alteration of POLDIP3 Splicing Associated with Loss of Function of TDP-43 in Tissues Affected with ALS

Shiga, Atsushi; Ishihara, Tomohiko; Miyashita, Akinori; Kuwabara, Misaki; Kato, Taisuke; Watanabe, Norihiro; Yamahira, Akie; Kondo, Chigusa; Yokoseki, Akio; Takahashi, Masuhiro; Kuwano, Ryozo; Kakita, Akiyoshi; Nishizawa, Masatoyo; Takahashi, Hitoshi; Onodera, Osamu

doi:10.1371/journal.pone.0043120

Cited by 77 publications

(79 citation statements)

References 33 publications

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“…3c). We also evaluated splicing in TDP-43 target genes POLDIP3/SKAR, STAG2, and FNIP1 [11, 14, 55], but found no changes in their respective splicing profiles (Supplemental Fig. 3c).…”

Section: Resultsmentioning

confidence: 99%

The phosphatase calcineurin regulates pathological TDP-43 phosphorylation

et al. 2016

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Detergent insoluble inclusions of TDP-43 protein are hallmarks of the neuropathology in over 90% of amyotrophic lateral sclerosis (ALS) cases and approximately half of frontotemporal dementia (FTLD-TDP) cases. In TDP-43 proteinopathy disorders, lesions containing aggregated TDP-43 protein are extensively post-translationally modified, with phosphorylated TDP-43 (pTDP) being the most consistent and robust marker of pathological TDP-43 deposition. Abnormally phosphorylated TDP-43 has been hypothesized to mediate TDP-43 toxicity in many neurodegenerative disease models. To date several different kinases have been implicated in the genesis of pTDP, but no phosphatases have been shown to reverse pathological TDP-43 phosphorylation. We have identified the phosphatase calcineurin as an enzyme binding to and catalyzing the removal of pathological C-terminal phosphorylation of TDP-43 in vitro. In C. elegans models of TDP-43 proteinopathy, genetic elimination of calcineurin results in accumulation of excess pTDP, exacerbated motor dysfunction, and accelerated neurodegenerative changes. In cultured human cells, treatment with FK506 (tacrolimus), a calcineurin inhibitor, results in accumulation of pTDP species. Lastly, calcineurin co-localizes with pTDP in degenerating areas of the central nervous system in subjects with FTLD-TDP and ALS. Taken together these findings suggest calcineurin acts on pTDP as a phosphatase in neurons. Furthermore, patient treatment with calcineurin inhibitors may have unappreciated adverse neuropathological consequences.

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“…3c). We also evaluated splicing in TDP-43 target genes POLDIP3/SKAR, STAG2, and FNIP1 [11, 14, 55], but found no changes in their respective splicing profiles (Supplemental Fig. 3c).…”

Section: Resultsmentioning

confidence: 99%

The phosphatase calcineurin regulates pathological TDP-43 phosphorylation

et al. 2016

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“…TDP-43 was first shown to repress the inclusion of exon 9 in the CFTR gene by binding to long UG-rich sequences [16] and subsequently shown to act as both a splicing enhancer and repressor [17–19]. TDP-43 and FUS have both been shown to bind a set of overlapping RNA targets [20].…”

Section: Introductionmentioning

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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“…In order to study the effect of TDP-43 depletion on gene expression, several groups used a microarray approach to map transcriptional changes, whether on cell lines (Ayala et al, 2008;Fiesel et al, 2010;Bose et al, 2011;Tollervey et al, 2011;Shiga et al, 2012;Yu et al, 2012;Park et al, 2013;Honda et al, 2014) or animal models (Hazelett et al, 2012), or RNA-seq (Polymenidou et al, 2011). Here we present the effect of TDP-43 depletion at the level of the proteome.…”

Section: Introductionmentioning

confidence: 99%