ABHD12 and LPCAT3 Interplay Regulates a Lyso-phosphatidylserine-C20:4 Phosphatidylserine Lipid Network Implicated in Neurological Disease

PHARC
(polyneuropathy, hearing loss, cerebellar ataxia, retinitis
pigmentosa, and cataract) is a human neurological disorder caused
by deleterious mutations in the ABHD12 gene, which
encodes an integral membrane lyso-phosphatidylserine (lyso-PS) lipase.
Pharmacological or genetic disruption of ABHD12 leads to higher levels
of lyso-PS lipids in human cells and the central nervous system (CNS)
of mice. ABHD12 loss also causes rapid rewiring of PS content, resulting
in selective increases in the level of arachidonoyl (C20:4) PS and
decreases in the levels of other PS species. The biochemical basis
for ABHD12-dependent PS remodeling and its pathophysiological significance
remain unknown. Here, we show that genetic deletion of the lysophospholipid
acyltransferase LPCAT3 blocks accumulation of brain C20:4 PS in mice
lacking ABHD12 and concurrently produces hyper-increases in the level
of lyso-PS in these animals. These lipid changes correlate with exacerbated
auditory dysfunction and brain microgliosis in mice lacking both ABHD12
and LPCAT3. Taken together, our findings reveal that ABHD12 and LPCAT3
coordinately regulate lyso-PS and C20:4 PS content in the CNS and
point to lyso-PS lipids as the likely bioactive metabolites contributing
to PHARC-related neuropathologies.