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

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…

• MG
  Massachusetts General Hospital
• BF
  BrightFocus Foundation

  Awards: RF1NS124203, R01NS112503
• NI
  National Institutes of Health

  Awards: T32 GM008666, CA034196, GM008666
• NI
  National Institute of Neurological Disorders and Stroke