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Brown, Anna-Leigh; Wilkins, Oscar G.; Keuss, Matthew J.; Hill, Sarah E.; Zanovello, Matteo; Lee, Weaverly Colleen; Bampton, Alexander; Lee, Flora C. Y.; Masino, Laura; Qi, Yue A.; Bryce-Smith, Sam; Gatt, Ariana; Hallegger, Martina; Fagegaltier, Delphine; Phatnani, Hemali; Phatnani, Hemali; Kwan, Justin; Sareen, Dhruv; Broach, James R.; Simmons, Zachary; Arcila-Londono, Ximena; Lee, Edward B.; Van Deerlin, Vivianna M.; Shneider, Neil A.; [...]

TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A

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  • Medientyp: E-Artikel
  • Titel: TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A
  • Beteiligte: Brown, Anna-Leigh; Wilkins, Oscar G.; Keuss, Matthew J.; Hill, Sarah E.; Zanovello, Matteo; Lee, Weaverly Colleen; Bampton, Alexander; Lee, Flora C. Y.; Masino, Laura; Qi, Yue A.; Bryce-Smith, Sam; Gatt, Ariana; Hallegger, Martina; Fagegaltier, Delphine; Phatnani, Hemali; Phatnani, Hemali; Kwan, Justin; Sareen, Dhruv; Broach, James R.; Simmons, Zachary; Arcila-Londono, Ximena; Lee, Edward B.; Van Deerlin, Vivianna M.; Shneider, Neil A.; [...]
  • Erschienen: Springer Science and Business Media LLC, 2022
  • Erschienen in: Nature
  • Sprache: Englisch
  • DOI: 10.1038/s41586-022-04436-3
  • ISSN: 0028-0836; 1476-4687
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>Variants of <jats:italic>UNC13A</jats:italic>, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia<jats:sup>1–3</jats:sup>, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-43<jats:sup>4,5</jats:sup>. Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in <jats:italic>UNC13A</jats:italic>, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic <jats:italic>UNC13A</jats:italic> polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which <jats:italic>UNC13A</jats:italic> variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.</jats:p>