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 lpa(1). Then, modulating lpa(1)-mediated signalling might affect disease
progression in the ALS SOD1-G93A mouse model.Methods The influence of lpa-lpa(1) signalling
on the electrical properties, Ca2+ dynamic and survival of MNs was tested in vitro.
Expression of lpa(1) 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(1)
(siRNA(lpa1)) or with the lpa(1) 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 lpa(1).
Lpa-lpa(1) signalling evoked an excitotoxic response in MNs via voltage-sensitive
calcium channels. Cultured SOD1-G93A MNs displayed lpa(1) upregulation and heightened
vulnerability to lpa. In transgenic mice, lpa(1) was upregulated mostly in spinal
cord MNs before cell loss. Chronic administration of either siRNA(lpa1) or AM095 reduced
lpa(1) 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-lpa(1)
signalling contributes to MN degeneration in SOD1-G93A mice. Consequently, disrupting
lpa(1) slows down disease progression. This highlights LPA(1) signalling as a potential
target and/or biomarker in ALS.
