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Updated: Nov 19, 2025
A Quick Phenotypic Neurological Scoring System for Evaluating Disease Progression in the SOD1-G93A Mouse Model of ALS
Published on: October 6, 2015
Interfering with lysophosphatidic acid receptor edg2/lpa1 signalling slows down disease progression in SOD1-G93A
Ángela Gento-Caro1,2, Esther Vilches-Herrando1,2, Victoria García-Morales1,2
1Grupo de Neurodegeneración y Neurorreparación (GRUNEDERE), Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain.
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.
Insights
Targeting lysophosphatidic acid receptor 1 (LPA1) signaling in Amyotrophic Lateral Sclerosis (ALS) motor neurons (MNs) shows promise. Inhibiting LPA1 in SOD1-G93A mice improved motor function and extended lifespan, suggesting LPA1 as a therapeutic target.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Amyotrophic Lateral Sclerosis (ALS) is characterized by motor neuron (MN) excitability alterations.
- Lysophosphatidic acid (LPA) signaling via G-protein-coupled receptor LPA1 is a potential regulator of MN excitability.
Purpose of the Study:
- To investigate the role of LPA-LPA1 signaling in MN excitability and survival.
- To evaluate the therapeutic potential of targeting LPA1 in an ALS mouse model (SOD1-G93A).
Main Methods:
- In vitro analysis of LPA-LPA1 signaling effects on MNs (electrical properties, calcium dynamics, survival).
- Analysis of LPA1 expression in cultured MNs and spinal cords of SOD1-G93A mice.
- In vivo treatment of ALS mice with LPA1 inhibitors (siRNA or AM095) and evaluation of motor skills, MN loss, and lifespan.
Main Results:
- LPA increased MN excitability by modulating potassium channels, leading to excitotoxicity.
- LPA1 was upregulated in SOD1-G93A MNs and spinal cords.
- LPA1 inhibition (siRNA or AM095) delayed MN death, improved motor function, and prolonged survival in ALS mice.
Conclusions:
- Dysregulated LPA-LPA1 signaling contributes to MN degeneration in ALS.
- Disrupting LPA1 signaling slows ALS progression in a mouse model.
- LPA1 represents a potential therapeutic target and biomarker for ALS.
