RT journal article
T1 Interfering with lysophosphatidic acid receptor edg2/lpa1 signalling slows down disease progression in SOD1-G93A transgenic mice
A1 Gento Caro, Angela
A1 Vilches Herrando, Esther
A1 Garcia Morales, Victoria
A1 Portillo Pacheco, Federico Luis
A1 Rodríguez Bey, Guillermo
A1 González Forero, David
A1 Moreno López, Bernardo
A2 BiomedicinaBiotecnología y Salud Pública
K1 SOD1-G93A model
K1 amyotrophic lateral sclerosis
K1 background potassium channels
K1 excitotoxicity
K1 intrinsic membrane excitability
K1 lpa1/edg2/vzg1
K1 neurodegeneration
K1 neuroprotection
AB Aims: Alterations in excitability represent an early hallmark in Amyotrophic Lateral Sclerosis (ALS). Therefore, deciphering the factors that impact motor neuron (MN) excitability offers an opportunity to uncover further aetiopathogenic mechanisms, neuroprotective agents, therapeutic targets, and/or biomarkers in ALS. Here, we hypothesised that the lipokine lysophosphatidic acid (lpa) regulates MN excitability via the G-protein-coupled receptor lpa1 . Then, modulating lpa1 -mediated signalling might affect disease progression in the ALS SOD1-G93A mouse model.Methods: The influence of lpa-lpa1 signalling on the electrical properties, Ca2+ dynamic and survival of MNs was tested in vitro. Expression of lpa1 in cultured MNs and in the spinal cord of SOD1-G93A mice was analysed. ALS mice were chronically treated with a small-interfering RNA against lpa1 (siRNAlpa1 ) or with the lpa1 inhibitor AM095. Motor skills, MN loss, and lifespan were evaluated.Results: AM095 reduced MN excitability. Conversely, exogenous lpa increased MN excitability by modulating task1 'leak' potassium channels downstream of lpa1 . Lpa-lpa1 signalling evoked an excitotoxic response in MNs via voltage-sensitive calcium channels. Cultured SOD1-G93A MNs displayed lpa1 upregulation and heightened vulnerability to lpa. In transgenic mice, lpa1 was upregulated mostly in spinal cord MNs before cell loss. Chronic administration of either siRNAlpa1 or AM095 reduced lpa1 expression at least in MNs, delayed MN death, improved motor skills, and prolonged life expectancy of ALS mice.Conclusions: These results suggest that stressed lpa-lpa1 signalling contributes to MN degeneration in SOD1-G93A mice. Consequently, disrupting lpa1 slows down disease progression. This highlights LPA1 signalling as a potential target and/or biomarker in ALS.
PB Wiley
SN 1365-2990, 0305-1846
YR 2021
FD 2021-01-28
LK http://hdl.handle.net/10498/37872
UL http://hdl.handle.net/10498/37872
LA eng
DS Repositorio Institucional de la Universidad de Cádiz
RD 21-sep-2026