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
Masegosa, Vera (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Fritz, Elsa (Universidad Andrés Bello)
Corvalan, Daniela (Universidad Andrés Bello)
Rojas, Fabiola (Universidad Andrés Bello)
Garcés, Polett (Universidad Andrés Bello)
Navarro, X. (Xavier) (Universitat Autònoma de Barcelona. Institut de Neurociències)
Bloms-Funke, Petra (Grünenthal GmbH)
van Zundert, Brigitte (Universidad Andrés Bello)
Herrando-Grabulosa, Mireia (Universitat Autònoma de Barcelona. Institut de Neurociències)

Data:	2025
Resum:	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.
Nota:	Altres ajuts: acords transformatius de la UAB
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	GRT-X ; Astrocyte conditioned medium ; Amyotrophic lateral sclerosis ; Frontotemporal dementia ; Motoneuron death ; Oxidative and excitotoxity stress
Publicat a:	ACS chemical neuroscience, Vol. 16, Issue 15 (July 2025) , p. 2887-2900, ISSN 1948-7193

DOI: 10.1021/acschemneuro.5c00197
PMID: 40671688

14 p, 10.1 MB

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