Mechanism of <i>STMN2</i> 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, Maximiliano 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 Rita Agra de Almeida Quadros, Paayman Jafar-nejad, Frank Rigo, C. Frank Bennett, Cathleen Lutz, Clotilde Lagier‐Tourenne, Don W. Cleveland
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.