TY - JOUR
T1 - Mutation in the RRM2 domain of TDP-43 in amyotrophic lateral sclerosis with rapid progression associated with ubiquitin positive aggregates in cultured motor neurons
AU - Maurel, Cindy
AU - Madji-Hounoum, Blandine
AU - Thepault, Rose Anne
AU - Marouillat, Sylviane
AU - Brulard, Céline
AU - Danel-Brunaud, Véronique
AU - Camdessanche, Jean Philippe
AU - Blasco, Helene
AU - Corcia, Philippe
AU - Andres, Christian R.
AU - Vourc'h, Patrick
PY - 2018/1/2
Y1 - 2018/1/2
N2 - 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.
AB - 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.
KW - aggregates
KW - ALS
KW - TDP-43
KW - ubiquitin
UR - http://www.scopus.com/inward/record.url?scp=85023741654&partnerID=8YFLogxK
U2 - 10.1080/21678421.2017.1349152
DO - 10.1080/21678421.2017.1349152
M3 - Article
C2 - 28705014
AN - SCOPUS:85023741654
VL - 19
SP - 149
EP - 151
JO - Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
JF - Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
SN - 2167-8421
IS - 1-2
ER -