Research Summary

Functional characterization of a deregulated lysophospholipid pathway in a human neurological disease.

PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, cataract) is a rare genetic neurological disorder in humans caused by deleterious mutations to the Abhd12 gene. The Abhd12 gene codes for the serine hydrolase enzyme ABHD12, which serves as the principal lysophosphatidylserine (lyso-PS) lipase in the mammalian brain, thereby terminating lyso-PS mediated signaling. We recently discovered another serine hydrolase enzyme ABHD16A (also known as BAT5), that functions upstream of ABHD12, and biosynthesizes lyso-PS lipids in the central nervous system (CNS) and innate immune system from phosphatidylserine (PS) precursors. Our findings thus illuminate a new lyso-PS nodal axis in humans. Both ABHD12 and ABHD16A have high expression and activity in the CNS and immune system (see figure 1), and so do the recently deorphanized putative lyso-PS receptors from the GPCR family: GPR34, GPR174 and P2Y10. Taken together, the lyso-PS class of lipid transmitters have several unsolved problems and biological mechanisms in broad neuro(immunological) processes like PHARC, which we are very interested in studying.

Figure Legend: The schematic representation of the ABHD12/ABHD16A-lyso-PS pathway.