A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS–FTD

Although loss of TAR DNA-binding protein 43 kDa (TDP-43) splicing repression is well documented in postmortem tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), whether this abnormality occurs during early-stage disease remains unresolved. Cryptic exon inclusion reflects loss of function of TDP-43, and thus detection of proteins containing cryptic exon-encoded neoepitopes in cerebrospinal fluid (CSF) or blood could reveal the earliest stages of TDP-43 dysregulation in patients. Here we use a newly characterized monoclonal antibody specific to a TDP-43-dependent cryptic epitope (encoded by the cryptic exon found in HDGFL2) to show that loss of TDP-43 splicing repression occurs in…

• NS
  National Science Foundation

  Awards: 1920103, OAC 1920103
• AA
  Alzheimer's Association
• AA
  ALS Association
• RA
  Richard and Susan Smith Family Foundation
• B
  Biogen
• UO
  University of California, Santa Cruz
• JH
  Johns Hopkins University
• TA
  Target ALS
• NI
  National Institutes of Health

  Awards: R01NS095969, R33NS115161, UH3NS115608, P30AG066507
• NI
  National Institute on Aging

  Award: 1ZIAAG000933
• NH
  National Heart, Lung, and Blood Institute
• NI
  National Institute of Neurological Disorders and Stroke

  Award: R01NS095969
• RP
  Robert Packard Center for ALS Research, Johns Hopkins University