Interfering with lysophosphatidic acid receptor edg2/lpa1 signalling slows down disease progression in SOD1-G93A transgenic mice

Abstract

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 (siRNA_lpa1 ) 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 siRNA_lpa1 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.

Keywords: SOD1-G93A model; amyotrophic lateral sclerosis; background potassium channels; excitotoxicity; intrinsic membrane excitability; lpa1/edg2/vzg1; neurodegeneration; neuroprotection.