The Spastic Paraplegia-Associated Phospholipase DDHD1 Is a Primary Brain Phosphatidylinositol Lipase

Deleterious mutations in the serine
hydrolase DDHD domain containing
1 (DDHD1) cause the SPG28 subtype of the neurological disease hereditary
spastic paraplegia (HSP), which is characterized by axonal neuropathy
and gait impairments. DDHD1 has been shown to display PLA1-type phospholipase
activity with a preference for phosphatidic acid. However, the endogenous
lipid pathways regulated by DDHD1 in vivo remain
poorly understood. Here we use a combination of untargeted and targeted
metabolomics to compare the lipid content of brain tissue from DDHD1+/+ and DDHD1–/– mice, revealing that
DDHD1 inactivation causes a substantial decrease in the level of polyunsaturated
lysophosphatidylinositol (LPI) lipids and a corresponding increase
in the level of phosphatidylinositol (PI) lipids. Levels of other
phospholipids were mostly unchanged, with the exception of decreases
in the levels of select polyunsaturated lysophosphatidylserine (LPS)
and lysophosphatidylcholine lipids and a striking remodeling of PI
phosphates (e.g., PIP and PIP2) in DDHD1–/– brain tissue. Biochemical assays confirmed that DDHD1 hydrolyzes
PI/PS to LPI/LPS with sn-1 selectivity and accounts
for a substantial fraction of the PI/PS lipase activity in mouse brain
tissue. These data indicate that DDHD1 is a principal regulator of
bioactive LPI and other lysophospholipids, as well as PI phosphates,
in the mammalian nervous system, pointing to a potential role for
these lipid pathways in HSP.