Mutation in the RRM2 domain of TDP-43 in amyotrophic lateral sclerosis with rapid progression associated with ubiquitin positive aggregates in cultured motor neurons

Cindy Maurel, Blandine Madji-Hounoum, Rose Anne Thepault, Sylviane Marouillat, Céline Brulard, Véronique Danel-Brunaud, Jean Philippe Camdessanche, Helene Blasco, Philippe Corcia, Christian R. Andres, Patrick Vourc'h*

*Corresponding author for this work

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Mutations in the TAR-DNA Binding Protein-43 (TDP-43) encoding the TARDBP gene are present in amyotrophic lateral sclerosis (ALS). TDP-43 is the major component of ubiquitin-positive inclusions in motor neurons in ALS patients. We report here a novel heterozygous missense mutation in TARDBP in an ALS patient presenting a rapid form of ALS. This mutation p.N259S is located within the RNA recognition motif 2 (RRM2) in very close proximity with nucleotides in RNA. It is the first time a mutation was reported in this RRM2 domain of TDP-43. Expression of TDP-43N259S in neuronal cells NSC-34 and in primary cultures of motor neurons was associated with cytoplasmic TDP-43/ubiquitin positive inclusions. Our findings identified for the first time a mutation in ALS in the RRM2 domain of TDP-43, reinforcing the link between this RNA-binding protein, perturbations in RNA metabolism, disruption in protein homeostasis and ALS.

Original languageEnglish
Pages (from-to)149-151
Number of pages3
JournalAmyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Volume19
Issue number1-2
DOIs
Publication statusPublished - 2 Jan 2018
Externally publishedYes

Keywords

  • aggregates
  • ALS
  • TDP-43
  • ubiquitin

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