Mutation in the RRM2 domain of TDP-43 in Amyotrophic Lateral Sclerosis with rapid progression associated with ubiquitin positive aggregates in cultured motor neurons

作者：Maurel Cindy; Madji Hounoum Blandine; Thepault Rose Anne; Marouillat Sylviane; Brulard Celine; Danel Brunaud Veronique; Camdessanche Jean Philippe; Blasco Helene; Corcia Philippe; Andres Christian R; Vourc'h Patrick^*

来源：Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2018, 19(1-2): 149-151.

DOI：10.1080/21678421.2017.1349152

• TDP-43
• ALS
• aggregates
• ubiquitin

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-43(N259S) 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.

• 出版日期2018