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Science ; 379(6637): 1140-1149, 2023 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-36927019

RESUMO

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.


Assuntos
Proteínas de Ligação a DNA , Edição de Genes , Poliadenilação , Splicing de RNA , Estatmina , Proteinopatias TDP-43 , Animais , Humanos , Camundongos , Proteínas de Ligação a DNA/metabolismo , Precursores de RNA/genética , Precursores de RNA/metabolismo , Estatmina/genética , Estatmina/metabolismo , Proteinopatias TDP-43/genética , Proteinopatias TDP-43/terapia , Sítios de Splice de RNA , Oligonucleotídeos Antissenso/genética , Crescimento Neuronal
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