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

• Published in: Science (American Association for the Advancement of Science) Vol. 379; no. 6637; pp. 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: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 17-03-2023
• 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
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abq5622

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.