Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies.
Science
; 379(6637): 1140-1149, 2023 03 17.
Article
en En
| MEDLINE
| ID: mdl-36927019
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.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Empalme del ARN
/
Poliadenilación
/
Proteínas de Unión al ADN
/
Estatmina
/
Proteinopatías TDP-43
/
Edición Génica
Idioma:
En
Revista:
Science
Año:
2023
Tipo del documento:
Article