Mechanism of <i>STMN2</i> cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies-Reference-Cited by-同舟云学术

Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies

Published:2023-03-17 Issue:6637 Volume:379 Page:1140-1149
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Baughn Michael W.¹²^ORCID,Melamed Ze’ev¹²³^ORCID,López-Erauskin Jone¹²,Beccari Melinda S.¹²^ORCID,Ling Karen⁴^ORCID,Zuberi Aamir⁵^ORCID,Presa Maximilliano⁵^ORCID,Gonzalo-Gil Elena⁵,Maimon Roy¹²,Vazquez-Sanchez Sonia¹²^ORCID,Chaturvedi Som²,Bravo-Hernández Mariana²^ORCID,Taupin Vanessa²,Moore Stephen²,Artates Jonathan W.¹²,Acks Eitan¹²,Ndayambaje I. Sandra⁶^ORCID,Agra de Almeida Quadros Ana R.⁶^ORCID,Jafar-nejad Paayman⁴^ORCID,Rigo Frank⁴,Bennett C. Frank⁴^ORCID,Lutz Cathleen⁵,Lagier-Tourenne Clotilde⁶⁷^ORCID,Cleveland Don W.¹²^ORCID

Affiliation:

1. Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA.

2. Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.

3. Department of Medical Neurobiology, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.

4. Ionis Pharmaceuticals, Carlsbad, CA 92010, USA.

5. Rare Disease Translational Center, The Jackson Laboratory, Bar Harbor, ME 04609, USA.

6. Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

7. Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/science.abq5622

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