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

Abstract

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.

Lipids in the Physiopathology of Hereditary Spastic Paraplegias

“…Knockout of Ddhd2 led to accumulation of triacylglycerol, and recombinant DDHD2 was revealed to have a triacylglycerol-lipase activity (Inloes et al, 2014). Recently, lipidomic analysis of the brain of Ddhd1 knockout mice showed that phosphatidylinositol and phosphatidylserine are the main physiological substrates of DDHD1 (Inloes et al, 2018). It is conceivable that DDHD1 and DDHD2 have different substrates depending on the cell type that is investigated.…”

“…of Ddhd1 in mice led to striking remodeling of phosphoinositides in the brain (Inloes et al, 2018). Furthermore, spastizin (ZFYVE26) mutated in SPG15 (Hanein et al, 2008) has a FYVE domain that mediates interaction with phosphatidylinositol-3phosphate (PI3P).…”

Phospholipases in neuronal function: A role in learning and memory?

“…DDHD1 has been shown to be regulated by phospholipid metabolites generated by other phospholipases (such as PA produced by PLD, which is discussed below) (Yamashita et al, ). Remarkably, although DDHD1 and DDHD2 share human disease relevance (mutations in either enzyme cause hereditary spastic paraplegia in humans), and related sequences, they do not appear to perform similar metabolic functions in vivo, but rather regulate a distinct class of lipids in the mammalian nervous system (Inloes et al, ; Inloes et al, ). The extracellular PLA 1 isoforms are (1) phosphatidylserine‐selective phospholipase A1 (PS‐PLA 1 ), (2) membrane‐associated phosphatidic acid‐selective phospholipase A1α and A1β (mPA‐PLA1α and mPA‐PLA1β respectively), (3) lipoprotein lipase (LPL, not to be confused with 1/2 acyl lysophospholipids 1‐LPL and 2‐LPL), (4) hepatic lipase (HL), (5) pancreatic lipase (PL), (6) endothelial lipase (EL) and vii) pancreatic lipase‐related protein‐1, ‐2 and ‐3 (PLPR1‐3), all of which display a variety of substrate specificities and functions.…”

“…The early metabolite of PLD activity on canonical phospholipids, PA, can be hydrolysed by phosphatidic acid‐preferring phospholipase DDHD1 (also known as PA‐PLA 1 ) to release saturated FFAs and LPA. The phospholipase DDHD1 has also been shown to hydrolyse phosphatidylinositol (PI) and PS to LPI and LPS with sn‐1 selectivity in the mouse (Inloes et al, ). The DDHD domain of the enzyme is crucial for the PLA 1 activity, as well as for phosphatidylinositol phosphate (PtdIns) binding and oligomerization (Inoue et al, ), which play crucial roles in membrane trafficking (Di Paolo and De Camilli, ; Vicinanza et al, ).…”

Specificity of Acyl Chain Composition of Phosphatidylinositols

“…PLA2 isoforms (over 30 isoforms identified) have been extensively characterized, mainly in regard to their role in arachidonic acid metabolism; however, a characterization of which isoform is involved in the remodeling of PI/PIPn has not been establish yet . On the other hand, mammals only have three PLA1 isoforms identified and recently it has been shown that PLA1 DDHD domain containing 1 (DDHD1) is involved in the remodeling of PI/PIPn with knockout of this enzyme in mice leading to an increase of 18:1 (oleoyl) in place of 18:0 acyl chain at sn‐1 position in PI/PIPn …”