|  Help  |  About  |  Contact Us

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

First Author  Baughn MW Year  2023
Journal  Science Volume  379
Issue  6637 Pages  1140-1149
PubMed ID  36927019 Mgi Jnum  J:334251
Mgi Id  MGI:7447372 Doi  10.1126/science.abq5622
Citation  Baughn MW, et al. (2023) Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies. Science 379(6637):1140-1149
abstractText  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.
Quick Links:
 
Quick Links:
 

Expression

Publication --> Expression annotations

 

Other

4 Bio Entities

Trail: Publication

0 Expression