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

Michael W. Baughn, Ze'ev Melamed*, Jone López-Erauskin, Melinda S. Beccari, Karen Ling, Aamir Zuberi, Maximilliano Presa, Elena Gonzalo-Gil, Roy Maimon, Sonia Vazquez-Sanchez, Som Chaturvedi, Mariana Bravo-Hernández, Vanessa Taupin, Stephen Moore, Jonathan W. Artates, Eitan Acks, I. Sandra Ndayambaje, Ana R. Agra de Almeida Quadros, Paayman Jafar-Nejad, Frank RigoC. Frank Bennett, Cathleen Lutz, Clotilde Lagier-Tourenne*, Don W. Cleveland*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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.

Original languageAmerican English
Pages (from-to)1140-1149
Number of pages10
JournalScience
Volume379
Issue number6637
DOIs
StatePublished - 17 Mar 2023

Bibliographical note

Publisher Copyright:
Copyright © 2023 The Authors, some rights reserved.

Fingerprint

Dive into the research topics of 'Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies'. Together they form a unique fingerprint.

Cite this