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 Rigo; C. Frank Bennett; Cathleen Lutz; Clotilde Lagier-Tourenne; Don W. Cleveland

doi:10.1126/science.abq5622

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

Department of Medical Neurobiology

Research output: Contribution to journal › Article › peer-review

48 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 language	English
Pages (from-to)	1140-1149
Number of pages	10
Journal	Science
Volume	379
Issue number	6637
DOIs	https://doi.org/10.1126/science.abq5622
State	Published - 17 Mar 2023

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Copyright © 2023 The Authors, some rights reserved.

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Baughn, M. W., Melamed, Z., López-Erauskin, J., Beccari, M. S., Ling, K., Zuberi, A., Presa, M., Gonzalo-Gil, E., Maimon, R., Vazquez-Sanchez, S., Chaturvedi, S., Bravo-Hernández, M., Taupin, V., Moore, S., Artates, J. W., Acks, E., Sandra Ndayambaje, I., Agra de Almeida Quadros, A. R., Jafar-Nejad, P., ... Cleveland, D. W. (2023). Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies. Science, 379(6637), 1140-1149. https://doi.org/10.1126/science.abq5622

@article{932864107dfc496abfd728568341afd4,

title = "Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies",

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.",

author = "Baughn, {Michael W.} and Ze'ev Melamed and Jone L{\'o}pez-Erauskin and Beccari, {Melinda S.} and Karen Ling and Aamir Zuberi and Maximilliano Presa and Elena Gonzalo-Gil and Roy Maimon and Sonia Vazquez-Sanchez and Som Chaturvedi and Mariana Bravo-Hern{\'a}ndez and Vanessa Taupin and Stephen Moore and Artates, {Jonathan W.} and Eitan Acks and {Sandra Ndayambaje}, I. and {Agra de Almeida Quadros}, {Ana R.} and Paayman Jafar-Nejad and Frank Rigo and {Frank Bennett}, C. and Cathleen Lutz and Clotilde Lagier-Tourenne and Cleveland, {Don W.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2023 The Authors, some rights reserved.",

year = "2023",

month = mar,

day = "17",

doi = "10.1126/science.abq5622",

language = "אנגלית",

volume = "379",

pages = "1140--1149",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6637",

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Baughn, MW, Melamed, Z, López-Erauskin, J, Beccari, MS, Ling, K, Zuberi, A, Presa, M, Gonzalo-Gil, E, Maimon, R, Vazquez-Sanchez, S, Chaturvedi, S, Bravo-Hernández, M, Taupin, V, Moore, S, Artates, JW, Acks, E, Sandra Ndayambaje, I, Agra de Almeida Quadros, AR, Jafar-Nejad, P, Rigo, F, Frank Bennett, C, Lutz, C, Lagier-Tourenne, C & Cleveland, DW 2023, 'Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies', Science, vol. 379, no. 6637, pp. 1140-1149. https://doi.org/10.1126/science.abq5622

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.

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.

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DO - 10.1126/science.abq5622

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AN - SCOPUS:85150312859

SN - 0036-8075

VL - 379

SP - 1140

EP - 1149

JO - Science

JF - Science

IS - 6637

ER -

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

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