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Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies.
Baughn, Michael W; Melamed, Ze'ev; López-Erauskin, Jone; Beccari, Melinda S; Ling, Karen; Zuberi, Aamir; Presa, Maximilliano; Gonzalo-Gil, Elena; Maimon, Roy; Vazquez-Sanchez, Sonia; Chaturvedi, Som; Bravo-Hernández, Mariana; Taupin, Vanessa; Moore, Stephen; Artates, Jonathan W; Acks, Eitan; Ndayambaje, I Sandra; Agra de Almeida Quadros, Ana R; Jafar-Nejad, Paayman; Rigo, Frank; Bennett, C Frank; Lutz, Cathleen; Lagier-Tourenne, Clotilde; Cleveland, Don W.
Afiliación
  • Baughn MW; Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA.
  • Melamed Z; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
  • López-Erauskin J; Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA.
  • Beccari MS; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
  • Ling K; Department of Medical Neurobiology, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
  • Zuberi A; Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA.
  • Presa M; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
  • Gonzalo-Gil E; Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA.
  • Maimon R; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
  • Vazquez-Sanchez S; Ionis Pharmaceuticals, Carlsbad, CA 92010, USA.
  • Chaturvedi S; Rare Disease Translational Center, The Jackson Laboratory, Bar Harbor, ME 04609, USA.
  • Bravo-Hernández M; Rare Disease Translational Center, The Jackson Laboratory, Bar Harbor, ME 04609, USA.
  • Taupin V; Rare Disease Translational Center, The Jackson Laboratory, Bar Harbor, ME 04609, USA.
  • Moore S; Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA.
  • Artates JW; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
  • Acks E; Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA.
  • Ndayambaje IS; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
  • Agra de Almeida Quadros AR; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
  • Jafar-Nejad P; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
  • Rigo F; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
  • Bennett CF; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
  • Lutz C; Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA.
  • Lagier-Tourenne C; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
  • Cleveland DW; Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA.
Science ; 379(6637): 1140-1149, 2023 03 17.
Article en En | MEDLINE | ID: mdl-36927019
Loss of nuclear TDP-43 is a hallmark of neurodegeneration in TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 mislocalization results in cryptic splicing and polyadenylation of pre-messenger RNAs (pre-mRNAs) encoding stathmin-2 (also known as SCG10), a protein that is required for axonal regeneration. We found that TDP-43 binding to a GU-rich region sterically blocked recognition of the cryptic 3' splice site in STMN2 pre-mRNA. Targeting dCasRx or antisense oligonucleotides (ASOs) suppressed cryptic splicing, which restored axonal regeneration and stathmin-2-dependent lysosome trafficking in TDP-43-deficient human motor neurons. In mice that were gene-edited to contain human STMN2 cryptic splice-polyadenylation sequences, ASO injection into cerebral spinal fluid successfully corrected Stmn2 pre-mRNA misprocessing and restored stathmin-2 expression levels independently of TDP-43 binding.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Empalme del ARN / Poliadenilación / Proteínas de Unión al ADN / Estatmina / Proteinopatías TDP-43 / Edición Génica Límite: Animals / Humans Idioma: En Revista: Science Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Empalme del ARN / Poliadenilación / Proteínas de Unión al ADN / Estatmina / Proteinopatías TDP-43 / Edición Génica Límite: Animals / Humans Idioma: En Revista: Science Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos