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

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 kno...

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Published in:Science (American Association for the Advancement of Science) 2023-03, Vol.379 (6637), p.1140-1149
Main Authors: 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
Format: Article
Language:English
Subjects:
Ablation
Amyotrophic lateral sclerosis
Anatomy
Animals
Antisense oligonucleotides
Binding sites
Blocking
Central nervous system
Cerebrospinal fluid
Coat protein
CRISPR
Dementia
Dementia disorders
DNA-Binding Proteins - metabolism
Frontotemporal dementia
Gene Editing
Gene expression
Genome editing
Genomes
Humans
Injuries
Literary Devices
Maintenance
Mice
Motor neurons
mRNA
Muscle contraction
Muscles
Neurodegenerative diseases
Neuromuscular junctions
Neuronal Outgrowth
Neurons
Oligonucleotides
Oligonucleotides, Antisense - genetics
Paralysis
Phages
Polyadenylation
Proteins
Regeneration
Ribonucleic acid
RNA
RNA Precursors - genetics
RNA Precursors - metabolism
RNA processing
RNA Splice Sites
RNA Splicing
RNA-binding protein
Skeletal muscle
Splicing
Stathmin
Stathmin - genetics
Stathmin - metabolism
TDP-43 Proteinopathies - genetics
TDP-43 Proteinopathies - therapy
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Summary: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 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 cryptic splice-polyadenylation sequences, ASO injection into cerebral spinal fluid successfully corrected pre-mRNA misprocessing and restored stathmin-2 expression levels independently of TDP-43 binding.
ISSN:0036-8075
1095-9203
1095-9203
DOI:10.1126/science.abq5622