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

• 成果类型: Article
• 署名作者: Baughn, Michael W.; Melamed, Ze'ev; Lopez-Erauskin, Jone; Beccari, Melinda S.; Ling, Karen; Zuberi, Aamir; Presa, Maximilliano; Gonzalo-Gil, Elena; Maimon, Roy; Vazquez-Sanchez, Sonia; Chaturvedi, Som; Bravo-Hernandez, Mariana; Taupin, Vanessa; Moore, Stephen; Artates, Jonathan W.; Acks, Eitan; Ndayambaje, I. Sandra; Quadros, Ana R. Agra de Almeida; Jafar-Nejad, Paayman; Rigo, Frank; Bennett, C. Frank; Lutz, Cathleen; Lagier-Tourenne, Clotilde; Cleveland, Don W.
• 署名单位: University of California System; University of California San Diego; Ludwig Institute for Cancer Research; University of California System; University of California San Diego; Hebrew University of Jerusalem; Ionis Pharmaceuticals, Inc.; Jackson Laboratory; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11914
• DOI: 10.1126/science.abq5622
• 发表日期: 2023-03-17
• 页码: 1140-1149
• 关键词: frontotemporal lobar degeneration; motor-neuron disease; microtubule dynamics; axonal-transport; rna; als; binding; protein; cleavage; aggregation

摘要

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.