Novel Dual Mechanism GRT-X Agonist Acting on Kv7 Potassium Channel/Translocator Protein Receptor Prevents Motoneuron Degeneration Following Exposure to Mouse and Human Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Astrocyte-Conditioned Media
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) form a continuous spectrum of aggressive neurodegenerative diseases affecting primarily motoneurons (MNs) and cortical frontotemporal neurons. Noncell autonomous mechanisms contribute to ALS/FTD, wherein astrocytes release toxic f...
| Autores: | , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Universitat Autònoma de Barcelona |
| Repositorio: | Dipòsit Digital de Documents de la UAB |
| Idioma: | inglés |
| OAI Identifier: | oai:ddd.uab.cat:318582 |
| Acceso en línea: | https://ddd.uab.cat/record/318582 https://dx.doi.org/urn:doi:10.1021/acschemneuro.5c00197 |
| Access Level: | acceso abierto |
| Palabra clave: | GRT-X Astrocyte conditioned medium Amyotrophic lateral sclerosis Frontotemporal dementia Motoneuron death Oxidative and excitotoxity stress |
| Sumario: | Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) form a continuous spectrum of aggressive neurodegenerative diseases affecting primarily motoneurons (MNs) and cortical frontotemporal neurons. Noncell autonomous mechanisms contribute to ALS/FTD, wherein astrocytes release toxic factor(s) detrimental to MNs. Because of the multifactorial nature of ALS, single-pathway-focused therapies have limited effectiveness in improving ALS. Therefore, novel combinatorial therapies are currently being pursued. Here, we evaluated whether the simultaneous activation of two complementary targets, the voltage-gated potassium channels 7.2/3 (Kv7.2/3) and the mitochondrial translocator protein (TSPO), by a novel synthesized compound (GRT-X) is an effective neuroprotective treatment in ALS in vitro models. We exposed primary rat ventral spinal cord neuronal cultures and rat spinal cord organotypic cultures to astrocyte-conditioned medium derived from primary mouse ALS astrocytes expressing mutant human SOD1 (SOD1-ACM) or from human-induced pluripotent stem cell (iPSC)-derived astrocytes carrying an ALS-causing mutation in SOD1 (SOD1-ACM) or an ALS/FTD-causing mutation in TDP-43 (TDP43-ACM). We report that the diverse human and mouse ALS/FTD-ACMs compromise the MN viability. Remarkably, GRT-X led to consistent protection of MNs. Moreover, ALS/FTD-ACM increases oxidative stress levels, which are prevented with GRT-X treatment. Together, we show that the complementary activation of TSPO and Kv7.2/3 may offer a novel therapeutic strategy for ALS/FTD due to its capacity to protect MNs from noncell-autonomous toxicity induced by diseased astrocytes. |
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