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Abstract
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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive muscle paralysis due to motor neuron degeneration in the brainstem and spinal cord, causing premature death, mainly owing to respiratory failure
We evaluated the effects of Tideglusib treatment on the levels of pTDP-43 in control and ALS lymphoblasts from sporadic ALS patients
A fatal motor degeneration disease that lacks an effective treatment, there is ais pressing need neuron to search for new therapies
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive muscle paralysis due to motor neuron degeneration in the brainstem and spinal cord, causing premature death, mainly owing to respiratory failure. The etiopathogenesis of ALS is still unclear involving altered signaling pathways such as mitochondrial dysfunction, glutamate excitotoxicity, oxidative stress, protein aggregation, and neuroinflammation. About 97% of patients show cytoplasmic inclusions in motor neurons containing TDP-43, the protein product of TARDBP gene [1]. This suggests that similar pathogenic mechanisms may be present in different ALS subtypes. TDP43 is mainly located in the nucleus, but under pathological conditions, it translocates to the cytoplasm where it suffers different post-translational modifications including hyperphosphorylation, ubiquitination, and truncation, leading to formation of toxic Cterminal TDP-43 fragments and protein aggregation [3].
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