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#36927019 2023/03/16 To Up
Mechanism of 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 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.
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