A panel of TDP-43-regulated splicing events verifies loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue

Cao, Maize C; Ryan, Brigid; Wu, Jane Y.; Curtis, Maurice A.; Faull, Richard L.M.; Dragunow, Michael; Scotter, Emma L.

doi:10.1016/j.nbd.2023.106245

Cited by 7 publications

(4 citation statements)

References 92 publications

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“…At the molecular level, we and others have shown that different C-terminal TDP-43 mutations, such as Q331K and M323K, can lead to a splicing gain of function when expressed at physiological levels ( Fratta et al, 2018 ). However, in TDP-43 pathology, TDP-43 exits the nucleus, leading to the loss of nuclear function including in splicing regulation and the appearance of pathological events such as cryptic exons that seem to define at least the end-stage of TDP-43 proteinopathies ( Cao et al, 2023 ; Ling et al, 2015 ; Ma et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

TDP-43-M323K causes abnormal brain development and progressive cognitive and motor deficits associated with mislocalised and increased levels of TDP-43

Godoy-Corchuelo,

Ali,

Brito Armas

et al. 2024

Neurobiology of Disease

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Section: Introductionmentioning

confidence: 99%

TDP-43-M323K causes abnormal brain development and progressive cognitive and motor deficits associated with mislocalised and increased levels of TDP-43

Godoy-Corchuelo,

Ali,

Brito Armas

et al. 2024

Neurobiology of Disease

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“…Five IPA events meet our enrichment criteria ( Fig. 2A ), including USP31 , which was identified in a targeted assay of sporadic ALS motor cortex tissue 28 . However, IPA events were generally more weakly enriched in TDP-43 depleted nuclei compared to 3’Ext and ALE events.…”

Section: Resultsmentioning

confidence: 99%

TDP-43 loss induces extensive cryptic polyadenylation in ALS/FTD

Bryce-Smith,

Brown,

Mehta

et al. 2024

Preprint

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Nuclear depletion and cytoplasmic aggregation of the RNA binding protein TDP-43 is the hallmark of ALS, occurring in over 97% of cases. A key consequence of TDP-43 nuclear loss is the de-repression of cryptic exons. Whilst TDP-43 regulated cryptic splicing is increasingly well catalogued, cryptic alternative polyadenylation (APA) events, which define the 3' end of last exons, have been largely overlooked, especially when not associated with novel upstream splice junctions. We developed a novel bioinformatic approach to reliably identify distinct APA event types: alternative last exons (ALE), 3'UTR extensions (3'Ext) and intronic polyadenylation (IPA) events. We identified novel neuronal cryptic APA sites induced by TDP-43 loss of function by systematically applying our pipeline to a compendium of publicly available and in house datasets. We find that TDP-43 binding sites and target motifs are enriched at these cryptic events and that TDP-43 can have both repressive and enhancing action on APA. Importantly, all categories of cryptic APA can also be identified in ALS and FTD post mortem brain regions with TDP-43 proteinopathy underlining their potential disease relevance. RNA-seq and Ribo-seq analyses indicate that distinct cryptic APA categories have different downstream effects on transcript and translation. Intriguingly, cryptic 3'Exts occur in multiple transcription factors, such as ELK1, SIX3, and TLX1, and lead to an increase in wild-type protein levels and function. Finally, we show that an increase in RNA stability leading to a higher cytoplasmic localisation underlies these observations. In summary, we demonstrate that TDP-43 nuclear depletion induces a novel category of cryptic RNA processing events and we expand the palette of TDP-43 loss consequences by showing this can also lead to an increase in normal protein translation.

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“…It is therefore hypothesized that dysregulation of RNA activity may be involved in the pathogenesis of ALS [4][5][6][7][8] . Accordingly, dysregulated splicing has been recently suggested to play an important role in pathogenesis because of the loss of normal TDP-43 [9][10][11][12] . However, other facets of RNA dysregulation are not fully explored.…”

Section: Introductionmentioning

confidence: 99%

A phase Ib/IIa randomized trial of Enoxacin in patients with ALS

Magen,

Kaneb,

Masnata

et al. 2024

Preprint

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The RNAse III DICER is essential for miRNA biogenesis. DICER activity is downregulated in sporadic and genetic forms of ALS. Accordingly, hundreds of miRNAs are broadly downregulated, and their mRNA targets are de-repressed. Enoxacin is a fluoroquinolone, which increases DICER activity and miRNA biogenesis. In an investigator-initiated, first-in- patient phase Ib/IIa study we tested Enoxacin safety and tolerability in patients with ALS and explored pharmacodynamic biomarkers for Enoxacin target engagement. Six patients with sporadic ALS were dosed with oral Enoxacin twice daily for 30 days. Patients did not experience any serious adverse events and completed the dosing period. Molecular analysis of cell-free miRNA in plasma and CSF revealed a global increase in plasma and CSF miRNA levels in all post-treatment time points, compared to baseline. Therefore, our study demonstrates that Enoxacin is tolerable and provides important evidence for in-patient target engagement. These results encourage testing Enoxacin efficacy in larger trials.

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A panel of TDP-43-regulated splicing events verifies loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue

Cited by 7 publications

References 92 publications

TDP-43-M323K causes abnormal brain development and progressive cognitive and motor deficits associated with mislocalised and increased levels of TDP-43

TDP-43-M323K causes abnormal brain development and progressive cognitive and motor deficits associated with mislocalised and increased levels of TDP-43

TDP-43 loss induces extensive cryptic polyadenylation in ALS/FTD

A phase Ib/IIa randomized trial of Enoxacin in patients with ALS

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