TY - JOUR
T1 - Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies
AU - Baughn, Michael W.
AU - Melamed, Ze'ev
AU - López-Erauskin, Jone
AU - Beccari, Melinda S.
AU - Ling, Karen
AU - Zuberi, Aamir
AU - Presa, Maximilliano
AU - Gonzalo-Gil, Elena
AU - Maimon, Roy
AU - Vazquez-Sanchez, Sonia
AU - Chaturvedi, Som
AU - Bravo-Hernández, Mariana
AU - Taupin, Vanessa
AU - Moore, Stephen
AU - Artates, Jonathan W.
AU - Acks, Eitan
AU - Sandra Ndayambaje, I.
AU - Agra de Almeida Quadros, Ana R.
AU - Jafar-Nejad, Paayman
AU - Rigo, Frank
AU - Frank Bennett, C.
AU - Lutz, Cathleen
AU - Lagier-Tourenne, Clotilde
AU - Cleveland, Don W.
N1 - Publisher Copyright:
Copyright © 2023 The Authors, some rights reserved.
PY - 2023/3/17
Y1 - 2023/3/17
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85150312859
U2 - 10.1126/science.abq5622
DO - 10.1126/science.abq5622
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C2 - 36927019
AN - SCOPUS:85150312859
SN - 0036-8075
VL - 379
SP - 1140
EP - 1149
JO - Science
JF - Science
IS - 6637
ER -