1. Mutation in the RRM2 domain of TDP-43 in Amyotrophic Lateral Sclerosis with rapid progression associated with ubiquitin positive aggregates in cultured motor neurons
- Author
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Patrick Vourc'h, Philippe Corcia, Cindy Maurel, Christian R. Andres, Sylviane Marouillat, Jean Philippe Camdessanche, Hélène Blasco, Rose Anne Thépault, Véronique Danel-Brunaud, Céline Brulard, and Blandine Madji-Hounoum
- Subjects
0301 basic medicine ,Male ,Mutation, Missense ,Biology ,medicine.disease_cause ,TARDBP ,03 medical and health sciences ,0302 clinical medicine ,Fatal Outcome ,Ubiquitin ,mental disorders ,medicine ,Missense mutation ,Humans ,Amyotrophic lateral sclerosis ,Cells, Cultured ,Inclusion Bodies ,Motor Neurons ,Mutation ,RNA recognition motif ,Amyotrophic Lateral Sclerosis ,nutritional and metabolic diseases ,RNA ,Middle Aged ,medicine.disease ,nervous system diseases ,Cell biology ,DNA-Binding Proteins ,030104 developmental biology ,Neurology ,Cytoplasm ,biology.protein ,Disease Progression ,Neurology (clinical) ,030217 neurology & neurosurgery - 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.
- Published
- 2017