Dysregulation of RNA Splicing in Tauopathies

Apicco, Daniel J.; Zhang, Cheng; Maziuk, Brandon F.; Jiang, Lulu; Ballance, Heather; Boudeau, Samantha; Ung, Choong Yong; Li, Hu; Wolozin, Benjamin

doi:10.1016/j.celrep.2019.11.093

Cited by 58 publications

(49 citation statements)

References 71 publications

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“…It has also been hypothesized that mutant tau mislocalizes to the somatodendritic compartment, where it alters RBP function (Vanderweyde et al, 2016). In the tau-P301S mouse, aggregation of RBPs with tau, and resulting alterations in splicing, converge on pathways associated with synaptic transmission (Apicco et al, 2019), similar to the effect we observed in tau-V337M organoids. These mice exhibit increased inclusion of exon 14 of the AMPA receptor subunit GRIA2 (Apicco et al, 2019), which we also observed in tau-V337M organoids.…”

Section: Discussionsupporting

confidence: 79%

Glutamatergic dysfunction precedes neuron loss in cerebral organoids withMAPTmutation

Bowles

Whitney

et al. 2021

Preprint

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Frontotemporal dementia (FTD) due to MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations due to the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, and glutamatergic signaling pathways and regulators including the RNA-binding protein ELAVL4. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function and build-up of tau and P-tau S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons of layers affected in patients. Mutant neurons are susceptible to glutamate toxicity which was rescued pharmacologically by treatment with the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede cell death, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD.

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Section: Discussionsupporting

confidence: 79%

Glutamatergic dysfunction precedes neuron loss in cerebral organoids withMAPTmutation

Bowles

Whitney

et al. 2021

Preprint

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“…RNA-seq has demonstrated that significant dysfunction on RNA splicing occurs in the PS19 tau mouse model and in AD brain [51]. In addition, reduced expression of an RNA binding protein TIA1 normalized some of the impaired disease-related RNA splicing [51]. Based on the analysis of the…”

Section: Discussionmentioning

confidence: 99%

hnRNP A1 Regulates Alternative Splicing of Tau Exon 10 by Targeting 3′ Splice Sites

Liu

Kim

Choi

et al. 2020

Cells

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The ratio control of 4R-Tau/3R-Tau by alternative splicing of Tau exon 10 is important for maintaining brain functions. In this study, we show that hnRNP A1 knockdown induces inclusion of endogenous Tau exon 10, conversely, overexpression of hnRNP A1 promotes exon 10 skipping of Tau. In addition, hnRNP A1 inhibits splicing of intron 9, but not intron 10. Furthermore, hnRNP A1 directly interacts with the 3′ splice site of exon 10 to regulate its functions in alternative splicing. Finally, gene ontology analysis demonstrates that hnRNP A1-induced splicing and gene expression targets a subset of genes with neuronal function.

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“…In agreement, loss of dTau, resulted in elevated translation and protein synthesis as reflected by the increased expression of translation machinery components, including initiation factors, proteins which control gene expression or silencing and ribosomal proteins. Spliceosome disruption and altered pre-mRNA processing are also emerging as potential contributors to Tau-mediated neurodegeneration [52] . On the other hand, transgenic Tau elevation by expression of human Tau in the fly CNS, triggered the reduction of multiple spliceosomal proteins [53] .…”

Section: Resultsmentioning

confidence: 99%

NORMA-The network makeup artist: a web tool for network annotation visualization

Koutrouli

Karatzas

Papanikolopoulou

et al. 2020

Preprint

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NORMA is a web tool for interactive network annotation visualization and topological analysis, able to handle multiple networks and annotations simultaneously. Precalculated annotations (e.g. Gene Ontology/Pathway enrichment or clustering results) can be uploaded and visualized in a network either as colored pie-chart nodes or as color-filled convex hulls in a Venn-diagram-like style. In the case where no annotation exists, algorithms for automated community detection are offered. Users can adjust the network views using standard layout algorithms or allow NORMA to slightly modify them for visually better group separation. Once a network view is set, users can interactively select and highlight any group of interest in order to generate publication-ready figures. Briefly, with NORMA, users can encode three types of information simultaneously. These are: i) the network, ii) the communities or annotations and iii) node categories or expression values. Finally, NORMA offers basic topological analysis and direct topological comparison across any of the selected networks. NORMA service is available at:

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Dysregulation of RNA Splicing in Tauopathies

Cited by 58 publications

References 71 publications

Glutamatergic dysfunction precedes neuron loss in cerebral organoids withMAPTmutation

Glutamatergic dysfunction precedes neuron loss in cerebral organoids withMAPTmutation

hnRNP A1 Regulates Alternative Splicing of Tau Exon 10 by Targeting 3′ Splice Sites

NORMA-The network makeup artist: a web tool for network annotation visualization

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