2019
DOI: 10.15252/embj.2018100989
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Abnormal TDP ‐43 function impairs activity‐dependent BDNF secretion, synaptic plasticity, and cognitive behavior through altered Sortilin splicing

Abstract: Aberrant function of the RNA‐binding protein TDP‐43 has been causally linked to multiple neurodegenerative diseases. Due to its large number of targets, the mechanisms through which TDP‐43 malfunction cause disease are unclear. Here, we report that knockdown, aggregation, or disease‐associated mutation of TDP‐43 all impair intracellular sorting and activity‐dependent secretion of the neurotrophin brain‐derived neurotrophic factor (BDNF) through altered splicing of the trafficking receptor Sortilin. Adult mice … Show more

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Cited by 33 publications
(28 citation statements)
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“…Loss of TDP-43 leads to the generation of isoform owing to additional exon 17b and soluble Sortilin protein. Therefore, a study by Tann et al hypothesized that TDP-43 dysfunction caused by mutations in TARDBP gene altered BDNF secretion and synaptic plasticity [77]. In a mouse model, the authors confirmed that hippocampal CA1-specific knockout of TDP-43 increased exon 17b mRNA of sort1 mRNA and reduced dendrite complexity and spine.…”
Section: Tar-binding Protein Gene (Tardbp)mentioning
confidence: 93%
“…Loss of TDP-43 leads to the generation of isoform owing to additional exon 17b and soluble Sortilin protein. Therefore, a study by Tann et al hypothesized that TDP-43 dysfunction caused by mutations in TARDBP gene altered BDNF secretion and synaptic plasticity [77]. In a mouse model, the authors confirmed that hippocampal CA1-specific knockout of TDP-43 increased exon 17b mRNA of sort1 mRNA and reduced dendrite complexity and spine.…”
Section: Tar-binding Protein Gene (Tardbp)mentioning
confidence: 93%
“…It has a known role in regulating brain-derived neurotrophic factor (BDNF), which is essential for synaptic plasticity, neuronal survival as well as differentiation [127]. Tann et al ( 2019) successfully corrected M337V mutation in TDP-43 M337V -iPSCs using CRISPR/Cas9 and proved that M337V mutation impairs BDNF secretion and synaptic plasticity through altering Sortilin splicing [128]. Gene editing using CRISPR/Cas9 has opened a new avenue of therapeutic approach for ALS.…”
Section: Targeting Tardbpmentioning
confidence: 99%
“…Previous studies showed that these four genes [MADD (38), STAG2 (39), FNIP1 (40), and BRD8 (41)] were potentially important for tumors. In mice models, abnormal TDP-43 function, owing to aggregation or diseaseassociated mutation, induced the wrong splicing of trafficking receptor sortilin (42), the loss of which promoted cell proliferation of lung cancer cells (43). Similarly, TDP-43 also regulated lncRNA expression.…”
Section: Tdp-43-mediated Mrna Splicingmentioning
confidence: 99%