Interfering with lysophosphatidic acid receptor edg2/lpa 1 signalling slows down disease progression in SOD1-G93A transgenic mice

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 lpa . Then, modulating lpa -mediated signalling might affect disease progression in the ALS SOD1-G93A mouse model. The influence of lpa-lpa signalling on the electrical properties, Ca dynamic and survival of MNs was tested in vitro. Expression of lpa 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 lpa (siRNA ) or with the lpa inhibitor AM095. Motor skills, MN loss, and lifespan were evaluated. AM095 reduced MN excitability. Conversely, exogenous lpa increased MN excitability by modulating task1 'leak' potassium channels downstream of lpa . Lpa-lpa signalling evoked an excitotoxic response in MNs via voltage-sensitive calcium channels. Cultured SOD1-G93A MNs displayed lpa upregulation and heightened vulnerability to lpa. In transgenic mice, lpa was upregulated mostly in spinal cord MNs before cell loss. Chronic administration of either siRNA or AM095 reduced lpa expression at least in MNs, delayed MN death, improved motor skills, and prolonged life expectancy of ALS mice. These results suggest that stressed lpa-lpa signalling contributes to MN degeneration in SOD1-G93A mice. Consequently, disrupting lpa slows down disease progression. This highlights LPA signalling as a potential target and/or biomarker in ALS.