TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis

Jemeen Sreedharan, Ian P Blair, Vineeta B Tripathi, Xun Hu, Caroline Vance, Boris Rogelj, Steven Ackerley, Jennifer C Durnall, Kelly L Williams, Emanuele Buratti, Francisco Baralle, Jacqueline de Belleroche, J Douglas Mitchell, P Nigel Leigh, Ammar Al-Chalabi, Christopher C Miller, Garth Nicholson, Christopher E Shaw

Research output: Contribution to journalArticlepeer-review

2093 Citations (Scopus)


Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.

Original languageEnglish
Pages (from-to)1668-1672
Number of pages5
Issue number5870
Early online date28 Feb 2008
Publication statusPublished - 21 Mar 2008


  • Adult
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Amyotrophic Lateral Sclerosis
  • Animals
  • Apoptosis
  • CHO Cells
  • Chick Embryo
  • Chromosomes, Human, Pair 1
  • Cricetinae
  • Cricetulus
  • DNA-Binding Proteins
  • Embryonic Development
  • Female
  • Humans
  • Male
  • Microsatellite Repeats
  • Middle Aged
  • Molecular Sequence Data
  • Mutant Proteins
  • Mutation, Missense
  • Neurons
  • Journal Article
  • Research Support, Non-U.S. Gov't


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