RT Journal Article
T1 Tideglusib, a Non-ATP Competitive Inhibitor of GSK-3β as a Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis
A1 Martínez González, Loreto
A1 Gonzalo Consuegra, Claudia
A1 Gómez Almería, Marta
A1 Porras, Gracia
A1 Lago Femia, Eva de
A1 Martín Requero, Ángeles
A1 Martínez, Ana
AB Amyotrophic Lateral Sclerosis (ALS) is the most common degenerative motor neuron disease in adults. About 97% of ALS patients present TDP-43 aggregates with post-translational modifications, such as hyperphosphorylation, in the cytoplasm of affected cells. GSK-3β is one of the protein kinases involved in TDP-43 phosphorylation. Up-regulation of its expression and activity is reported on spinal cord and cortex tissues of ALS patients. Here, we propose the repurposing of Tideglusib, an in-house non-ATP competitive GSK-3β inhibitor that is currently in clinical trials for autism and myotonic dystrophy, as a promising therapeutic strategy for ALS. With this aim we have evaluated the efficacy of Tideglusib in different experimental ALS models both in vitro and in vivo. Moreover, we observed that GSK-3β activity is increased in lymphoblasts from sporadic ALS patients, with a simultaneous increase in TDP-43 phosphorylation and cytosolic TDP-43 accumulation. Treatment with Tideglusib decreased not only phospho-TDP-43 levels but also recovered its nuclear localization in ALS lymphoblasts and in a human TDP-43 neuroblastoma model. Additionally, we found that chronic oral treatment with Tideglusib is able to reduce the increased TDP-43 phosphorylation in the spinal cord of Prp-hTDP-43A315T mouse model. Therefore, we consider Tideglusib as a promising drug candidate for ALS, being proposed to start a clinical trial phase II by the end of the year.
PB MPDI
SN 1422-0067
YR 2021
FD 2021-08-20
LK https://hdl.handle.net/20.500.14352/4843
UL https://hdl.handle.net/20.500.14352/4843
LA eng
NO Ministerio de Ciencia e Innovación (MICINN)
NO Instituto de Salud Carlos III (ISCIII)
NO Comunidad de Madrid
DS Docta Complutense
RD 3 may 2024