TDP-43 represses cryptic exon inclusion in the FTD–ALS gene UNC13A

Abstract A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord 1 . A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing 2–4 . Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies 5,6 , but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon-splicing event in UNC13A . Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons…

• AA
  ALS Association
• BF
  BrightFocus Foundation

  Award: A2020279F
• TS
  Takeda Science Foundation
• RC
  Rainwater Charitable Foundation
• NI
  National Institutes of Health

  Awards: U01AG057195, P01AG019724, P30AG062422, W81XWH, R35NS097263, U19AG063911
• UO
  University of California, San Francisco

  Award: P01AG019724
• SR
  Stanford Research Computing Center, Stanford University