Affinage

PLA2G6

85/88 kDa calcium-independent phospholipase A2 · UniProt O60733

Length
806 aa
Mass
89.9 kDa
Annotated
2026-04-28
100 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PLA2G6 encodes calcium-independent phospholipase A2β (iPLA2β), a multifunctional lipid-metabolizing enzyme that cleaves sn-2 acyl chains—with preference for oxidized and polyunsaturated fatty acids including 15-HpETE-PE and DHA—from glycerophospholipids and also possesses acyl-CoA thioesterase activity, serving as a critical guardian of membrane lipid homeostasis and a major suppressor of ferroptosis (PMID:10092647, PMID:33542532, PMID:18937505). iPLA2β maintains mitochondrial inner membrane integrity, supports retromer-mediated lipid and protein recycling through direct interaction with Vps35/Vps26, regulates store-operated Ca²⁺ entry, and modulates ER stress responses; its loss leads to ceramide accumulation, mitochondrial cristae degeneration, impaired autophagy, and progressive neurodegeneration (PMID:29909971, PMID:26755131, PMID:25950622, PMID:16407316). In pancreatic β-cells, iPLA2β amplifies glucose-stimulated insulin secretion by suppressing Kv2.1 delayed rectifier currents and prolonging Ca²⁺ oscillations (PMID:17895289, PMID:11278673). Loss-of-function mutations in PLA2G6 cause infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation, while dystonia-parkinsonism (PARK14) mutations selectively impair hydrolysis of the ferroptotic death signal 15-HpETE-PE, leading to its accumulation and progressive dopaminergic neuron loss (PMID:20886109, PMID:33542532, PMID:30088174).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1999 High

    Molecular cloning established that PLA2G6 encodes a Ca²⁺-independent phospholipase A2 with two catalytically active splice isoforms differing in ATP responsiveness, defining the enzyme's fundamental identity and regulatory properties.

    Evidence cDNA cloning from human pancreatic islets with recombinant protein expression and in vitro phospholipase assays

    PMID:10092647

    Open questions at the time
    • Three-dimensional structure not determined
    • Endogenous substrate specificity in vivo not yet defined
    • Oligomeric state and regulation by ankyrin repeats not characterized
  2. 2001 High

    Demonstration that iPLA2β amplifies glucose-stimulated insulin secretion and translocates to perinuclear compartments upon cAMP signaling established a regulated signaling role beyond housekeeping phospholipid remodeling.

    Evidence Overexpression in INS-1 cells, BEL inhibition, immunocytofluorescence, and insulin secretion assays

    PMID:11278673 PMID:11882502

    Open questions at the time
    • Identity of lipid mediators linking iPLA2β to secretory machinery unknown
    • Mechanism of cAMP-induced translocation unresolved
  3. 2002 High

    Enantioselective inhibitor studies discriminated iPLA2β from iPLA2γ in intact cells, showing iPLA2β specifically mediates receptor-coupled arachidonic acid release in smooth muscle, establishing isoform-selective signaling.

    Evidence S-BEL vs R-BEL enantiomers in A-10 cells with arachidonic acid release measurement

    PMID:12089145

    Open questions at the time
    • Downstream eicosanoid products of iPLA2β-released AA in smooth muscle not fully mapped
    • Whether iPLA2γ compensates in iPLA2β absence not tested
  4. 2006 High

    Identification that iPLA2β activates during mitochondrial membrane depolarization and promotes outer membrane rupture and cytochrome c release revealed a direct role in mitochondrial permeability transition, linking the enzyme to apoptotic signaling.

    Evidence Isolated mitochondria assays with BEL inhibition, membrane potential measurement, and cytochrome c release

    PMID:16407316 PMID:18936091

    Open questions at the time
    • Whether iPLA2β acts on specific mitochondrial phospholipid species (e.g., cardiolipin) not determined
    • Mechanism of iPLA2β activation by depolarization unknown
  5. 2007 High

    Gain- and loss-of-function mouse models proved iPLA2β amplifies insulin secretion in vivo by suppressing Kv2.1 currents and prolonging Ca²⁺ oscillations, defining an electrophysiological mechanism for its β-cell function.

    Evidence RIP-iPLA2β transgenic and iPLA2β-null mice with patch-clamp electrophysiology, Ca²⁺ imaging, and glucose tolerance tests

    PMID:17895289

    Open questions at the time
    • Specific lipid mediator that modulates Kv2.1 not identified
    • Whether this mechanism operates in human islets not confirmed
  6. 2008 Medium

    Discovery of an acyl-CoA thioesterase activity distinct from phospholipase activity expanded iPLA2β's enzymatic repertoire and linked it to mitochondrial fatty acid oxidation in skeletal muscle.

    Evidence iPLA2β-null mice with palmitate oxidation assays and chromatographic separation of thioesterase activity

    PMID:18937505

    Open questions at the time
    • Structural basis for dual enzymatic activities not resolved
    • Relative contribution of thioesterase vs phospholipase activity in different tissues unknown
    • Not independently replicated
  7. 2009 High

    An ENU-generated point mutation in the ankyrin repeat domain that abolished catalytic activity was sufficient to produce INAD with tubulovesicular spheroids, proving that loss of enzymatic function—not a structural scaffolding defect—drives disease.

    Evidence ENU mutagenesis mouse with neuropathology, electron microscopy, and biochemical activity assay

    PMID:19893029

    Open questions at the time
    • Whether ankyrin repeat mutations also disrupt protein-protein interactions not tested
    • Specific lipid substrates accumulating in INAD not identified
  8. 2010 High

    Biochemical analysis of disease-associated mutations revealed a genotype-activity correlation: INAD/NBIA mutations ablate catalytic activity while dystonia-parkinsonism mutations preserve or even increase it, suggesting distinct pathomechanisms for the two disease spectra.

    Evidence Purified recombinant WT and mutant PLA2G6 with in vitro phospholipase and lysophospholipase assays

    PMID:20886109

    Open questions at the time
    • Substrate specificity differences between dystonia-parkinsonism mutants not yet explored with oxidized lipid substrates
    • In vivo lipid profiles of dystonia-parkinsonism mutants not determined
  9. 2015 High

    Cross-species studies in Drosophila and patient fibroblasts established that PLA2G6 loss causes mitochondrial respiratory chain dysfunction, elevated lipid peroxidation, and Golgi/glycosylation defects, with deuterated PUFAs providing partial rescue—identifying lipid peroxidation as a druggable pathogenic driver.

    Evidence Drosophila iPLA2-VIA KO with respirometry, patient fibroblasts with glycosylation analysis, and deuterated PUFA rescue

    PMID:26001724 PMID:26668131

    Open questions at the time
    • Whether Golgi defects are secondary to lipid peroxidation or an independent pathway unclear
    • Mechanism by which PLA2G6 maintains Golgi morphology not defined
  10. 2016 High

    Demonstration that PLA2G6 deficiency impairs store-operated Ca²⁺ entry, causing autophagic dysfunction and progressive dopaminergic neuron loss, established a Ca²⁺ signaling–autophagy axis as a central pathogenic mechanism in PLA2G6-associated parkinsonism.

    Evidence Patient-derived cells and Pla2g6 exon2 KO mouse with Ca²⁺ imaging, autophagy assays, and dopaminergic neuron counting

    PMID:26755131

    Open questions at the time
    • Molecular mechanism by which iPLA2β regulates SOCE channels not identified
    • Whether Ca²⁺ and ferroptosis pathways converge or operate independently unknown
  11. 2018 High

    Discovery that iPLA2β physically binds retromer subunits Vps35/Vps26 and that its loss triggers a ceramide-driven positive feedback loop impairing retromer function revealed a non-enzymatic scaffolding role in membrane trafficking.

    Evidence Drosophila iPLA2-VIA KO with co-immunoprecipitation, lipidomics, genetic epistasis with vps26/vps35, and pharmacological ceramide reduction

    PMID:29909971

    Open questions at the time
    • Whether the retromer interaction requires iPLA2β catalytic activity not determined
    • Binding interface between iPLA2β and retromer not mapped
    • Whether this interaction occurs in mammalian neurons not confirmed
  12. 2019 High

    Lipidomic analysis showed iPLA2-VIA loss shortens phospholipid acyl chains causing ER stress, and that linoleic acid supplementation corrects lipid composition and suppresses α-synuclein aggregation, directly linking membrane lipid remodeling to synucleinopathy.

    Evidence Drosophila KO with mass spectrometry lipidomics, ER stress markers, transgenic rescue with WT vs A80T mutant, and linoleic acid supplementation

    PMID:31548400

    Open questions at the time
    • Whether acyl-chain shortening occurs in mammalian PLA2G6-deficient neurons not confirmed
    • Mechanism by which altered lipid composition promotes α-synuclein aggregation not defined
  13. 2021 High

    Identification of 15-HpETE-PE as the specific ferroptotic substrate of iPLA2β, and demonstration that the PD-associated R747W mutation selectively impairs its hydrolysis causing 15-HpETE-PE accumulation and parkinsonian motor deficits in knock-in mice, unified the ferroptosis-suppression and neurodegeneration functions into a single molecular mechanism.

    Evidence Lipidomics, CRISPR knock-in R748W mouse, patient fibroblast enzymatic assays, GPX4-null cell models, and xenograft tumor models

    PMID:33087576 PMID:33542532 PMID:34131139

    Open questions at the time
    • Whether ferroptosis is the dominant cell death mode in all PLA2G6-associated diseases or only in parkinsonism not resolved
    • Structural basis for substrate selectivity of PD mutants unknown
    • Therapeutic window for ferroptosis inhibitors in PLA2G6 disease not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for iPLA2β's dual enzymatic activities and substrate selectivity, the precise relationship between its retromer-binding, Ca²⁺-signaling, and anti-ferroptotic functions in dopaminergic neurons, and whether these represent parallel or convergent pathogenic axes.
  • No crystal structure of full-length iPLA2β available
  • Relative contribution of ferroptosis vs autophagy vs ER stress to neurodegeneration not delineated
  • No therapeutic strategy validated in human PLA2G6-associated disease

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 6 GO:0008289 lipid binding 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005739 mitochondrion 6 GO:0005634 nucleus 3 GO:0005783 endoplasmic reticulum 2 GO:0005829 cytosol 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1430728 Metabolism 7 R-HSA-5357801 Programmed Cell Death 5 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-162582 Signal Transduction 3 R-HSA-9612973 Autophagy 2 R-HSA-5653656 Vesicle-mediated transport 1
Partners
KCNB1VPS26VPS35
Complex memberships
retromer (via Vps35/Vps26 binding)

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Human PLA2G6 (iPLA2β) gene on chromosome 22q13.1 produces two catalytically active isoforms (85-kDa short and 88-kDa long) via exon-skipping alternative splicing of exon 8; both are active without Ca2+ and inhibited by bromoenol lactone, but only the long isoform is activated by ATP. cDNA cloning from human pancreatic islets, recombinant protein expression, in vitro phospholipase assay, alternative splicing analysis The Journal of biological chemistry High 10092647
2001 iPLA2β (PLA2G6) amplifies glucose-stimulated insulin secretion in pancreatic β-cells; cAMP-elevating agents promote translocation of iPLA2β to perinuclear/nuclear compartments, consistent with a signaling rather than housekeeping role. Stable overexpression in INS-1 insulinoma cells, insulin secretion assay, immunocytofluorescence, BEL inhibitor studies The Journal of biological chemistry High 11278673
2002 iPLA2β (PLA2G6), but not iPLA2γ, mediates arginine vasopressin-induced arachidonic acid release from A-10 smooth muscle cells, demonstrated using enantioselective inhibitors (S-BEL selective for iPLA2β, R-BEL selective for iPLA2γ). Enantioselective BEL inhibition in intact A-10 cells, arachidonic acid release assay, chiral HPLC separation of BEL enantiomers The Journal of biological chemistry High 12089145
2002 Stimulation of insulin secretion promotes time-dependent nuclear accumulation of iPLA2β in INS-1 cells; nuclear accumulation correlates with increased nuclear iPLA2β enzymatic activity and is attenuated by inhibitors of protein phosphorylation and glycosylation. Immunofluorescence, immunoaffinity fractionation, enzymatic activity assay in nuclear fractions, pharmacological inhibition American journal of physiology. Endocrinology and metabolism Medium 11882502
2003 Pancreatic islets and 832/13 INS-1 insulinoma cells express a novel ~70 kDa isoform of iPLA2β not generated by alternative splicing, which retains catalytic activity and participates in insulin secretion but not membrane phospholipid remodeling. Western blotting, mass spectrometry of tryptic peptides, BEL inhibition of insulin secretion, arachidonic acid incorporation assay Biochemistry High 14636061
2004 ER stress-induced apoptosis of insulin-secreting cells is amplified by iPLA2β overexpression and suppressed by BEL inhibition; ER stress activates iPLA2β, causes its perinuclear accumulation, and triggers caspase-3-mediated cleavage of 84 kDa iPLA2β to a 62 kDa nuclear fragment; ceramide accumulation is also iPLA2β-dependent. INS-1 cell overexpression, BEL inhibition, caspase activity assay, immunofluorescence, ceramide measurement Biochemistry High 14744135
2004 FcγRI activation in human monocytic U937 cells couples specifically to iPLA2β (not cPLA2α) for arachidonic acid release and generation of leukotriene B4 and prostaglandin E2; iPLA2β activation in this pathway is protein kinase C-dependent. BEL inhibition, siRNA/antisense knockdown, arachidonic acid release assay, eicosanoid measurement The Journal of biological chemistry Medium 15007079
2005 ER-localized iPLA2 activity in kidney, heart, and brain microsomes is attributable to iPLA2γ (group VIB), not iPLA2β, based on isoform-selective BEL enantiomers and immunoblot analysis. Subcellular fractionation, iPLA2 activity assay, immunoblotting, RT-PCR, BEL enantiomer inhibition Biochemical and biophysical research communications Medium 15629460
2006 Mitochondrial Ca2+-independent phospholipase A2 (iPLA2β) is activated during sustained mitochondrial membrane depolarization and Ca2+ accumulation; sustained activity promotes outer mitochondrial membrane rupture and spontaneous cytochrome c release; BEL inhibition of this phospholipase attenuates the mitochondrial permeability transition. Isolated mitochondria, membrane potential measurement, BEL inhibition, cytochrome c release assay, permeability transition pore assay The Journal of biological chemistry High 16407316
2007 iPLA2β (PLA2G6) plays a pivotal role in angiotensin II-induced transcriptional upregulation of RGS2 in vascular smooth muscle cells; both arachidonic acid and lysophosphatidylcholine (products of iPLA2β) induce RGS2 mRNA, and the pathway is abolished by pharmacological inhibition, antisense knockdown, or genetic deletion of iPLA2β. BEL inhibition, antisense oligonucleotides, iPLA2β-null mice VSMCs, adenoviral re-expression, RGS2 mRNA/protein measurement, iPLA2 enzymatic activity assay The Journal of biological chemistry High 17613534
2007 iPLA2β (PLA2G6) overexpression in pancreatic β-cells in vivo lowers blood glucose and amplifies glucose-induced insulin secretion; iPLA2β-null islets show blunted insulin secretion and impaired glucose tolerance; iPLA2β reduces Kv2.1 delayed rectifier current and prolongs glucose-induced action potentials and cytosolic Ca2+ elevations. Transgenic RIP-iPLA2β mice, iPLA2β-null mice, glucose tolerance test, patch-clamp electrophysiology, Ca2+ imaging, insulin secretion assay American journal of physiology. Endocrinology and metabolism High 17895289
2008 ER stress induces iPLA2β accumulation in mitochondria, opening of mitochondrial permeability transition pore, and loss of mitochondrial membrane potential in INS-1 cells; iPLA2β-mediated ceramide generation via sphingomyelin hydrolysis mediates mitochondrial dysfunction and cytochrome c release in the apoptotic cascade. Subcellular fractionation, mitochondrial membrane potential assay, cytochrome c release, ceramide measurement, iPLA2β overexpression, BEL and NSMase inhibition The Journal of biological chemistry High 18936091
2010 Human PLA2G6 enzyme hydrolyzes both phospholipids and lysophospholipids to release free fatty acids; INAD/NBIA mutations cause loss of enzymatic activity (<20% of WT), while dystonia-parkinsonism mutations do not impair catalytic activity and two produce increased specific activity for phospholipid substrates. Purified recombinant WT and mutant human PLA2G6, in vitro phospholipase and lysophospholipase assays with radiolabeled lipid substrates PloS one High 20886109
2010 iPLA2β undergoes endogenous proteolytic processing to generate N-terminally truncated isoforms that localize differentially to subcellular organelles; secretagogues and ER stress promote differential redistribution of iPLA2β variants among subcellular compartments. EGFP fusion protein stable expression, dual fluorescence organelle tracking, immunoblotting, mass spectrometry of N-terminal variants Biochimica et biophysica acta Medium 20132906
2010 iPLA2β deficiency in mice reduces brain DHA metabolism and DHA-dependent signaling in vivo at baseline and following muscarinic M1,3,5 receptor activation, consistent with iPLA2β selectively hydrolyzing DHA from phospholipids. iPLA2β-/- and +/- mice, intravenous [1-14C]DHA infusion, quantitative autoradiography of 81 brain regions, cholinergic agonist challenge Journal of lipid research High 20686114
2015 Knockout of the Drosophila PLA2G6 homolog iPLA2-VIA causes mitochondrial respiratory chain dysfunction, reduced ATP synthesis, abnormal mitochondrial morphology, and elevated mitochondrial lipid peroxidation; similar mitochondrial lipid peroxidation and membrane defects occur in fibroblasts from PLA2G6-mutant patients; deuterated PUFAs that inhibit lipid peroxidation partially rescue locomotor deficits. Drosophila iPLA2-VIA knockout, respirometry, ATP assay, electron microscopy, lipid peroxidation assay, patient fibroblast analysis, pharmacological rescue with deuterated PUFAs Brain : a journal of neurology High 26001724
2015 iPLA2β modulates Bcl-x pre-mRNA 5'-splice site selection to suppress anti-apoptotic Bcl-xL in β-cells; iPLA2β inactivation or knockdown augments the Bcl-xL/Bcl-xS ratio, whereas iPLA2β overexpression reduces it; the bioactive lipid 5(S)-HETE augments Bcl-xL/Bcl-xS by 15.5-fold. Chemical inactivation and siRNA knockdown of iPLA2β, transgenic and KO mouse islets, Bcl-x splice isoform quantitation by RT-PCR, exogenous lipid treatments The Journal of biological chemistry Medium 25762722
2015 In PLA2G6 knockout mice, mitochondria with damaged inner membranes appear early in neurons and move anterogradely into distal axons; inner mitochondrial membrane degeneration precedes axonal spheroid formation; presynaptic membrane abnormalities also develop, leading to axon terminal degeneration containing tubulovesicular structures. PLA2G6 KO mouse neuropathology, electron microscopy, immunohistochemistry, axonal transport analysis Neuropathology : official journal of the Japanese Society of Neuropathology Medium 25950622
2016 PLA2G6 deficiency impairs store-operated Ca2+ entry signaling; genetic or molecular impairment of PLA2G6-dependent Ca2+ signaling triggers autophagic dysfunction and progressive loss of dopaminergic neurons in substantia nigra pars compacta; this sequence is recapitulated in a Pla2g6 exon2 knockout mouse model. Patient-derived cells (idiopathic PD), PLA2g6 exon2 KO mouse, Ca2+ imaging, autophagy assays, dopaminergic neuron counting, L-DOPA behavioral rescue Nature communications High 26755131
2016 PLA2G6 deficiency causes elevated α-synuclein expression in neurons; phosphorylated α-synuclein accumulates in mitochondrial outer membrane-positive (TOM20+) granules in PLA2G6-KO mice; α-synuclein localizes to degenerated inner mitochondrial membranes, suggesting a role in stabilizing damaged mitochondrial membranes. PLA2G6 KO mouse, PLA2G6 knockdown cells, immunohistochemistry with TOM20 co-staining, immunofluorescence, electron microscopy, quantitative Lewy body analysis in PLAN and PD patients Acta neuropathologica communications Medium 27030050
2018 Loss of iPLA2-VIA (Drosophila PLA2G6 homolog) does not alter phospholipid composition of brain tissue but causes elevation in ceramide levels; iPLA2-VIA physically binds retromer subunits Vps35 and Vps26, enhancing retromer function to promote protein and lipid recycling; loss of iPLA2-VIA impairs retromer function, progressively increasing ceramide levels that in turn impair membrane fluidity and retromer function in a positive feedback loop. Drosophila iPLA2-VIA KO, lipidomics, co-immunoprecipitation of Vps35/Vps26, pharmacological ceramide reduction (myriocin, desipramine), genetic epistasis with vps26/vps35 mutants Cell metabolism High 29909971
2018 PARK14 mutant PLA2G6 proteins (D331Y, G517C, T572I, R632W, N659S, R741Q) fail to prevent rotenone-induced mitochondrial membrane potential loss, mitochondrial superoxide increase, complex I activity reduction, mitophagy impairment, and cytochrome c release, while WT PLA2G6 rescues all these defects. SH-SY5Y cell overexpression of WT and mutant PLA2G6, rotenone model, mitochondrial membrane potential assay, ROS measurement, complex I activity assay, ATP measurement, cytochrome c release, mitophagy markers Oncotarget Medium 29108286
2019 iPLA2-VIA loss in Drosophila shortens acyl-chain length of phospholipids, causing ER stress through membrane lipid disequilibrium; WT human iPLA2-VIA or the mitochondria-ER contact site protein C19orf12 rescue altered lipid composition, ER stress, and DA neurodegeneration; disease-associated iPLA2-VIA A80T mutant fails to rescue; linoleic acid supplementation corrects brain lipid composition and suppresses α-synuclein aggregation caused by iPLA2-VIA loss. Drosophila iPLA2-VIA KO, lipid analysis by mass spectrometry, ER stress markers, DA neuron counting, transgenic rescue with WT and A80T mutant, linoleic acid supplementation Proceedings of the National Academy of Sciences of the United States of America High 31548400
2020 PLA2G6 (iPLA2β/PNPLA9) metabolizes hydroperoxy-arachidonoyl- and adrenoyl-phosphatidylethanolamine (Hp-PE) to lyso-PE and oxidized fatty acid, attenuating ferroptotic injury; PLA2G6 protects human trophoblasts and mouse placenta from ferroptosis induced by GPX4 inhibition or hypoxia/reoxygenation. Primary human trophoblast cultures, mouse pregnancy model, GPX4 inhibitor (RSL3), hypoxia/reoxygenation, lipid mass spectrometry, PLA2G6 knockdown Proceedings of the National Academy of Sciences of the United States of America High 33087576
2021 iPLA2β (PLA2G6) hydrolyzes 15-HpETE-PE (the ferroptotic death signal generated by 15-LOX/PEBP1 complex) to avert ferroptosis; genetic or pharmacological inactivation of iPLA2β sensitizes cells to ferroptosis; patient fibroblasts with PD-associated mutation (R747W) show selectively decreased 15-HpETE-PE-hydrolyzing activity and elevated 15-HpETE-PE; Pnpla9 R748W knock-in mice develop progressive parkinsonian motor deficits with 15-HpETE-PE accumulation. Lipidomics (15-HpETE-PE quantification), CRISPR-Cas9 knock-in mouse (R748W), patient fibroblast assays, genetic and pharmacological iPLA2β inactivation, rotenone rat and SncaA53T mouse models Nature chemical biology High 33542532
2021 iPLA2β (PLA2G6) acts as a major ferroptosis repressor independent of GPX4 by detoxifying peroxidized lipids; iPLA2β-mediated removal of oxidized acyl tails from phospholipids suppresses p53-driven ferroptosis under ROS stress; iPLA2β loss has no obvious effect on normal development but is essential for regulating ferroptosis upon ROS-induced stress. GPX4-null cells, iPLA2β overexpression and inhibition, p53-driven ferroptosis assay, xenograft tumor model, lipid peroxidation measurement Nature communications High 34131139
2015 PLA2G6 loss causes disruption of Golgi morphology and defects in protein O-linked glycosylation and sialylation in patient fibroblasts; lentiviral re-expression of WT PLA2G6 rescues these Golgi and glycosylation abnormalities. Patient fibroblast cultures (INAD and dystonia-parkinsonism), HPLC and MALDI-TOF/MS glycosylation analysis, immunofluorescence of Golgi morphology, lentiviral WT PLA2G6 rescue Journal of medical genetics Medium 26668131
2008 iPLA2β (PLA2G6)-null mice show accelerated age-related bone loss associated with increased bone marrow adipogenesis and decreased osteogenesis; bone marrow stromal cells from KO mice express higher PPARγ and lower Runx2 mRNA, indicating that iPLA2β regulates mesenchymal stem cell lineage commitment. iPLA2β-null mice, bone morphometry, bone strength testing, osteoclast/osteoblast quantification, BMSC differentiation assays, gene expression analysis The American journal of pathology Medium 18349124
2008 iPLA2β activity is required for skeletal muscle fatty acid oxidation through an acyl-CoA thioesterase activity (distinct from its phospholipase activity) that liberates CoA-SH to facilitate fatty acid transport into mitochondria; iPLA2β-null mice show reduced palmitate oxidation and reduced acyl-CoA thioesterase activity. iPLA2β-null mice, palmitate oxidation assay, palmitoyl-CoA and acetyl-CoA oxidation assays, ATP and calmodulin column chromatography, BEL inhibition of thioesterase activity Biochemistry Medium 18937505
2017 PLA2G6 protein accumulates in the cores of brainstem-type Lewy bodies in PARK14 and idiopathic Parkinson's disease patients, but not in cortical Lewy bodies, multiple system atrophy, or Alzheimer's disease. Immunohistochemistry and immunoblotting on post-mortem brain tissue from PARK14, idiopathic PD, DLB, MSA, and AD Neuroscience letters Medium 28213071
2009 A point mutation in the ankyrin repeat domain of Pla2g6 (generated by ENU mutagenesis in mice) produces a protein with no glycerophospholipid-catalyzing enzyme activity and causes early-onset (7-8 weeks) INAD with widespread spheroid formation containing tubulovesicular membranes, demonstrating that loss of catalytic activity is sufficient for disease. ENU mutagenesis mouse model, neuropathology with electron microscopy, biochemical assay of iPLA2β enzyme activity The American journal of pathology High 19893029
2018 PARK14 D331Y knockin mice develop early-onset degeneration of substantia nigra dopaminergic neurons with Lewy body pathology, mitochondrial cristae disruption, mitochondrial dysfunction, elevated ROS, ER stress (upregulated GRP78, IRE1, PERK, CHOP), and impaired mitophagy (reduced parkin and BNIP3). PLA2G6 D331Y/D331Y knockin mouse, dopaminergic neuron counting, electron microscopy, mitochondrial membrane potential, ROS measurement, ER stress protein immunoblot, mitophagy protein expression, behavioral testing Molecular neurobiology High 30088174
2021 iPLA2β translocates to the ER upon myocardial ischemia/reperfusion injury; this translocation promotes ER stress and cardiomyocyte apoptosis; iPLA2β knockout or siRNA knockdown ameliorates ER stress and decreases cell death during I/R. iPLA2β KO mice, siRNA knockdown, I/R model in vivo and in vitro, cell surface protein biotinylation, immunofluorescence localization, ER stress markers, apoptosis assays Cells Medium 34207793

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Characterization of PLA2G6 as a locus for dystonia-parkinsonism. Annals of neurology 347 18570303
2021 iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4. Nature communications 288 34131139
2021 Phospholipase iPLA2β averts ferroptosis by eliminating a redox lipid death signal. Nature chemical biology 279 33542532
2010 Early-onset L-dopa-responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and spatacsin mutations. Movement disorders : official journal of the Movement Disorder Society 188 20669327
2008 Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN). Neurology 172 18443314
2010 Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations. Neurobiology of aging 164 20619503
2020 PLA2G6 guards placental trophoblasts against ferroptotic injury. Proceedings of the National Academy of Sciences of the United States of America 163 33087576
2015 Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction. Brain : a journal of neurology 158 26001724
2002 Identification of calcium-independent phospholipase A2 (iPLA2) beta, and not iPLA2gamma, as the mediator of arginine vasopressin-induced arachidonic acid release in A-10 smooth muscle cells. Enantioselective mechanism-based discrimination of mammalian iPLA2s. The Journal of biological chemistry 155 12089145
2018 Phospholipase PLA2G6, a Parkinsonism-Associated Gene, Affects Vps26 and Vps35, Retromer Function, and Ceramide Levels, Similar to α-Synuclein Gain. Cell metabolism 144 29909971
2010 Phenotypic spectrum of patients with PLA2G6 mutation and PARK14-linked parkinsonism. Neurology 117 20938027
2010 The roles of iPLA2, TRPM8 and TRPA1 in chemically induced cold hypersensitivity. Molecular pain 95 20092626
2008 H2O2-dependent hyperoxidation of peroxiredoxin 6 (Prdx6) plays a role in cellular toxicity via up-regulation of iPLA2 activity. The Journal of biological chemistry 95 18826942
1999 Human pancreatic islets express mRNA species encoding two distinct catalytically active isoforms of group VI phospholipase A2 (iPLA2) that arise from an exon-skipping mechanism of alternative splicing of the transcript from the iPLA2 gene on chromosome 22q13.1. The Journal of biological chemistry 94 10092647
2010 Catalytic function of PLA2G6 is impaired by mutations associated with infantile neuroaxonal dystrophy but not dystonia-parkinsonism. PloS one 92 20886109
2004 Apoptosis of insulin-secreting cells induced by endoplasmic reticulum stress is amplified by overexpression of group VIA calcium-independent phospholipase A2 (iPLA2 beta) and suppressed by inhibition of iPLA2 beta. Biochemistry 89 14744135
2018 PLA2G6-Associated Neurodegeneration (PLAN): Review of Clinical Phenotypes and Genotypes. Frontiers in neurology 85 30619057
2011 PLA2G6 gene mutation in autosomal recessive early-onset parkinsonism in a Chinese cohort. Neurology 85 21700586
2016 Impairment of PARK14-dependent Ca(2+) signalling is a novel determinant of Parkinson's disease. Nature communications 81 26755131
2008 Calcium-independent phospholipase A2 (iPLA2 beta)-mediated ceramide generation plays a key role in the cross-talk between the endoplasmic reticulum (ER) and mitochondria during ER stress-induced insulin-secreting cell apoptosis. The Journal of biological chemistry 81 18936091
2019 Parkinson's disease-associated iPLA2-VIA/PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling. Proceedings of the National Academy of Sciences of the United States of America 79 31548400
2013 Pantothenate kinase-associated neurodegeneration (PKAN) and PLA2G6-associated neurodegeneration (PLAN): review of two major neurodegeneration with brain iron accumulation (NBIA) phenotypes. International review of neurobiology 77 24209433
2009 R632W mutation in PLA2G6 segregates with dystonia-parkinsonism in a consanguineous Iranian family. European journal of neurology 77 19087156
2006 Passive calcium leak via translocon is a first step for iPLA2-pathway regulated store operated channels activation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 77 16611832
2001 Studies of insulin secretory responses and of arachidonic acid incorporation into phospholipids of stably transfected insulinoma cells that overexpress group VIA phospholipase A2 (iPLA2beta ) indicate a signaling rather than a housekeeping role for iPLA2beta. The Journal of biological chemistry 77 11278673
2014 PLA2G6-associated neurodegeneration (PLAN): further expansion of the clinical, radiological and mutation spectrum associated with infantile and atypical childhood-onset disease. Molecular genetics and metabolism 71 24745848
2006 Mitochondrial iPLA2 activity modulates the release of cytochrome c from mitochondria and influences the permeability transition. The Journal of biological chemistry 71 16407316
2014 PRDX6 promotes lung tumor progression via its GPx and iPLA2 activities. Free radical biology & medicine 67 24512906
2011 PLA2G6 mutations in PARK14-linked young-onset parkinsonism and sporadic Parkinson's disease. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 61 22213678
2008 Orai, STIM1 and iPLA2beta: a view from a different perspective. The Journal of physiology 60 18499724
2007 Glucose homeostasis, insulin secretion, and islet phospholipids in mice that overexpress iPLA2beta in pancreatic beta-cells and in iPLA2beta-null mice. American journal of physiology. Endocrinology and metabolism 56 17895289
2003 Oxidant-mediated AA release from astrocytes involves cPLA(2) and iPLA(2). Free radical biology & medicine 55 12788473
2007 Reticulocyte-secreted exosomes bind natural IgM antibodies: involvement of a ROS-activatable endosomal phospholipase iPLA2. Blood 53 17666570
2008 Age-related changes in bone morphology are accelerated in group VIA phospholipase A2 (iPLA2beta)-null mice. The American journal of pathology 51 18349124
2008 Clinical study and PLA2G6 mutation screening analysis in Chinese patients with infantile neuroaxonal dystrophy. European journal of neurology 50 19138334
2017 Dysfunction of PLA2G6 and CYP2C44-associated network signals imminent carcinogenesis from chronic inflammation to hepatocellular carcinoma. Journal of molecular cell biology 48 28655161
2010 Imaging decreased brain docosahexaenoic acid metabolism and signaling in iPLA(2)β (VIA)-deficient mice. Journal of lipid research 48 20686114
2009 Establishment of an improved mouse model for infantile neuroaxonal dystrophy that shows early disease onset and bears a point mutation in Pla2g6. The American journal of pathology 48 19893029
2012 Four novel rare mutations of PLA2G6 in Chinese population with Parkinson's disease. Parkinsonism & related disorders 47 23182313
2017 PARK14 PLA2G6 mutants are defective in preventing rotenone-induced mitochondrial dysfunction, ROS generation and activation of mitochondrial apoptotic pathway. Oncotarget 45 29108286
2015 Neuroaxonal dystrophy in PLA2G6 knockout mice. Neuropathology : official journal of the Japanese Society of Neuropathology 45 25950622
2016 High expression of α-synuclein in damaged mitochondria with PLA2G6 dysfunction. Acta neuropathologica communications 44 27030050
2018 PARK14 (D331Y) PLA2G6 Causes Early-Onset Degeneration of Substantia Nigra Dopaminergic Neurons by Inducing Mitochondrial Dysfunction, ER Stress, Mitophagy Impairment and Transcriptional Dysregulation in a Knockin Mouse Model. Molecular neurobiology 42 30088174
2013 New findings in a global approach to dissect the whole phenotype of PLA2G6 gene mutations. PloS one 42 24130795
2007 Group VIA phospholipase A2 (iPLA2beta) participates in angiotensin II-induced transcriptional up-regulation of regulator of g-protein signaling-2 in vascular smooth muscle cells. The Journal of biological chemistry 42 17613534
2014 Inhibition of Ca2+-independent phospholipase A2β (iPLA2β) ameliorates islet infiltration and incidence of diabetes in NOD mice. Diabetes 40 25213337
2022 Vitamin E prevents lipid peroxidation and iron accumulation in PLA2G6-Associated Neurodegeneration. Neurobiology of disease 39 35122944
2020 Genotype-phenotype correlations of adult-onset PLA2G6-associated Neurodegeneration: case series and literature review. BMC neurology 39 32183746
2011 Polymorphisms in nevus-associated genes MTAP, PLA2G6, and IRF4 and the risk of invasive cutaneous melanoma. Twin research and human genetics : the official journal of the International Society for Twin Studies 39 21962134
2010 Group VIA Ca2+-independent phospholipase A2 (iPLA2beta) and its role in beta-cell programmed cell death. Biochimie 39 20083151
2002 Stimulation of insulin secretion and associated nuclear accumulation of iPLA(2)beta in INS-1 insulinoma cells. American journal of physiology. Endocrinology and metabolism 39 11882502
2016 iPLA2β deficiency attenuates obesity and hepatic steatosis in ob/ob mice through hepatic fatty-acyl phospholipid remodeling. Biochimica et biophysica acta 38 26873633
2003 Pancreatic islets and insulinoma cells express a novel isoform of group VIA phospholipase A2 (iPLA2 beta) that participates in glucose-stimulated insulin secretion and is not produced by alternate splicing of the iPLA2 beta transcript. Biochemistry 38 14636061
2018 PLA2G6-associated neurodegeneration: New insights into brain abnormalities and disease progression. Parkinsonism & related disorders 37 30340910
2005 Identification and distribution of endoplasmic reticulum iPLA2. Biochemical and biophysical research communications 37 15629460
2012 Follow-up study of 25 Chinese children with PLA2G6-associated neurodegeneration. European journal of neurology 35 22934738
2011 PLA2G6 variant in Parkinson's disease. Journal of human genetics 35 21368765
2017 PLA2G6 accumulates in Lewy bodies in PARK14 and idiopathic Parkinson's disease. Neuroscience letters 32 28213071
2016 Genetic Analysis of PLA2G6 in 22 Indian Families with Infantile Neuroaxonal Dystrophy, Atypical Late-Onset Neuroaxonal Dystrophy and Dystonia Parkinsonism Complex. PloS one 32 27196560
2010 A link between endoplasmic reticulum stress-induced β-cell apoptosis and the group VIA Ca2+-independent phospholipase A2 (iPLA2β). Diabetes, obesity & metabolism 32 21029305
2018 iPLA2β and its role in male fertility, neurological disorders, metabolic disorders, and inflammation. Biochimica et biophysica acta. Molecular and cell biology of lipids 31 30408523
2004 The expression and function of a group VIA calcium-independent phospholipase A2 (iPLA2beta) in beta-cells. Canadian journal of physiology and pharmacology 31 15573142
2011 The PLA2G6 gene in early-onset Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society 30 21812034
2004 Fcgamma RI-triggered generation of arachidonic acid and eicosanoids requires iPLA2 but not cPLA2 in human monocytic cells. The Journal of biological chemistry 30 15007079
2020 Azoramide protects iPSC-derived dopaminergic neurons with PLA2G6 D331Y mutation through restoring ER function and CREB signaling. Cell death & disease 29 32071291
2016 Infantile neuroaxonal dystrophy and PLA2G6-associated neurodegeneration: An update for the diagnosis. Brain & development 29 27884548
2015 PKCδ-iPLA2-PGE2-PPARγ signaling cascade mediates TNF-α induced Claudin 1 expression in human lung carcinoma cells. Cellular signalling 29 25562426
2015 Disruption of Golgi morphology and altered protein glycosylation in PLA2G6-associated neurodegeneration. Journal of medical genetics 29 26668131
2014 Loss of presenilin 2 is associated with increased iPLA2 activity and lung tumor development. Oncogene 29 24858037
2013 Characterization of FKGK18 as inhibitor of group VIA Ca2+-independent phospholipase A2 (iPLA2β): candidate drug for preventing beta-cell apoptosis and diabetes. PloS one 29 23977134
2010 Evidence for proteolytic processing and stimulated organelle redistribution of iPLA(2)beta. Biochimica et biophysica acta 29 20132906
2010 Novel splice-site mutations and a large intragenic deletion in PLA2G6 associated with a severe and rapidly progressive form of infantile neuroaxonal dystrophy. Clinical genetics 29 20584031
2014 Infantile and childhood onset PLA2G6-associated neurodegeneration in a large North African cohort. European journal of neurology 28 25164370
2013 Genetic modulation of islet β-cell iPLA₂β expression provides evidence for its impact on β-cell apoptosis and autophagy. Islets 26 23411472
2018 Mutations in the Drosophila homolog of human PLA2G6 give rise to age-dependent loss of psychomotor activity and neurodegeneration. Scientific reports 25 29440694
2015 Neuroimaging studies and whole exome sequencing of PLA2G6-associated neurodegeneration in a family with intrafamilial phenotypic heterogeneity. Parkinsonism & related disorders 25 25634434
2014 Evidence of contribution of iPLA2β-mediated events during islet β-cell apoptosis due to proinflammatory cytokines suggests a role for iPLA2β in T1D development. Endocrinology 25 25004092
2010 iPLA2, a novel determinant in Ca2+- and phosphorylation-dependent S100A8/A9 regulated NOX2 activity. Biochimica et biophysica acta 25 20219570
2010 Proinflammatory treatment of astrocytes with lipopolysaccharide results in augmented Ca2+ signaling through increased expression of via phospholipase A2 (iPLA2). American journal of physiology. Cell physiology 25 21178110
2023 The role of the PLA2G6 gene in neurodegenerative diseases. Ageing research reviews 24 37236368
2018 Heterozygous PLA2G6 Mutation Leads to Iron Accumulation Within Basal Ganglia and Parkinson's Disease. Frontiers in neurology 24 30042723
2017 Alteration of mitochondrial protein PDHA1 in Lewy body disease and PARK14. Biochemical and biophysical research communications 24 28564592
2014 Urocortin affects migration of hepatic cancer cell lines via differential regulation of cPLA2 and iPLA2. Cellular signalling 23 24518041
2024 PRDX6-iPLA2 aggravates neuroinflammation after ischemic stroke via regulating astrocytes-induced M1 microglia. Cell communication and signaling : CCS 21 38287382
2018 PLA2G6-associated neurodegeneration presenting as a complicated form of hereditary spastic paraplegia. Journal of human genetics 21 30302010
2017 Ageing sensitized by iPLA2β deficiency induces liver fibrosis and intestinal atrophy involving suppression of homeostatic genes and alteration of intestinal lipids and bile acids. Biochimica et biophysica acta. Molecular and cell biology of lipids 21 28888832
2016 Clinical heterogeneity of PLA2G6-related Parkinsonism: analysis of two Saudi families. BMC research notes 21 27268037
2016 Validation of the finding of hypertrophy of the clava in infantile neuroaxonal dystrophy/PLA2G6 by biometric analysis. Neuroradiology 21 27516098
2015 Impaired corticostriatal LTP and depotentiation following iPLA2 inhibition is restored following acute application of DHA. Brain research bulletin 21 25562715
2012 Analysis of PLA2G6 gene mutation in sporadic early-onset parkinsonism patients from Chinese population. Neuroscience letters 21 22406380
2019 Early-Onset Parkinson's Disease Caused by PLA2G6 Compound Heterozygous Mutation, a Case Report and Literature Review. Frontiers in neurology 20 31496990
2014 iPLA2β knockout mouse, a genetic model for progressive human motor disorders, develops age-related neuropathology. Neurochemical research 19 24919816
2018 Novel PLA2G6 mutations and clinical heterogeneity in Chinese cases with phospholipase A2-associated neurodegeneration. Parkinsonism & related disorders 18 29454663
2017 Identification of the PLA2G6 c.1579G>A Missense Mutation in Papillon Dog Neuroaxonal Dystrophy Using Whole Exome Sequencing Analysis. PloS one 18 28107443
2016 Mutation screening of PLA2G6 in Japanese patients with early onset dystonia-parkinsonism. Journal of neural transmission (Vienna, Austria : 1996) 18 27942883
2021 iPLA2β Contributes to ER Stress-Induced Apoptosis during Myocardial Ischemia/Reperfusion Injury. Cells 17 34207793
2022 PLA2G6 Silencing Suppresses Melanoma Progression and Affects Ferroptosis Revealed by Quantitative Proteomics. Frontiers in oncology 16 35340268
2015 Group VIA Phospholipase A2 (iPLA2β) Modulates Bcl-x 5'-Splice Site Selection and Suppresses Anti-apoptotic Bcl-x(L) in β-Cells. The Journal of biological chemistry 16 25762722
2015 Increased iPLA2 activity and levels of phosphorylated GSK3B in platelets are associated with donepezil treatment in Alzheimer's disease patients. European archives of psychiatry and clinical neuroscience 16 25920742
2008 Skeletal muscle group VIA phospholipase A2 (iPLA2beta): expression and role in fatty acid oxidation. Biochemistry 16 18937505