Affinage

PLA2G6

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

Length
806 aa
Mass
89.9 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PLA2G6 encodes iPLA2β, a calcium-independent phospholipase A2 that hydrolyzes the sn-2 acyl chain of glycerophospholipids and is central to neuronal membrane homeostasis, lipid signaling, and protection from peroxidation-driven cell death (PMID:17033970, PMID:10092647). The gene produces two catalytically active isoforms by alternative splicing, with the long isoform being ATP-activated, and its activity requires an intact ankyrin repeat domain (PMID:10092647, PMID:19893029). Beyond canonical phospholipase activity, iPLA2β possesses fatty acyl-CoA thioesterase activity that supports fatty acid oxidation (PMID:18937505), and it selectively hydrolyzes DHA-containing phospholipids in vivo to supply DHA for brain signaling and corticostriatal synaptic plasticity (PMID:20686114, PMID:25562715). As a signaling enzyme, iPLA2β generates arachidonic acid and lysophospholipids that act through lipoxygenase pathways to drive RGS2 induction, vascular inflammation, and store-operated Ca2+ entry, and it couples specific stimuli (vasopressin, MCP-1, FcγRI) to lipid mediator production and directional cell behaviors including monocyte chemotaxis (PMID:12089145, PMID:17613534, PMID:18208975, PMID:18156193, PMID:22637477). In pancreatic β-cells iPLA2β amplifies insulin secretion and, under ER stress, translocates to the ER and mitochondria to drive a ceramide–mitochondrial permeability transition–caspase axis acting upstream of p38 MAPK, while also shifting Bcl-x pre-mRNA splicing toward the pro-apoptotic isoform (PMID:11278673, PMID:14744135, PMID:18936091, PMID:22194610, PMID:25762722); an analogous ER-translocation and apoptotic role operates in myocardial ischemia/reperfusion injury (PMID:34207793). A major protective function is the hydrolysis of the ferroptotic death signal 15-HpETE-PE, by which iPLA2β suppresses ferroptosis in a GPX4-independent manner and limits p53-driven and oxidative-stress-induced death (PMID:33087576, PMID:33542532, PMID:34131139). iPLA2β physically associates with the retromer subunits Vps35 and Vps26 to promote membrane recycling and prevent ceramide accumulation, and maintains phospholipid acyl-chain length to avert ER stress (PMID:29909971, PMID:31548400). Loss-of-function mutations that abolish enzyme activity cause infantile neuroaxonal dystrophy/NBIA, whereas mutations that spare general activity but selectively impair peroxidized-lipid hydrolysis cause Parkinson's disease through ferroptosis sensitization; the resulting pathology features mitochondrial inner-membrane degeneration, lipid peroxidation, and α-synuclein/Lewy body accumulation (PMID:19893029, PMID:20886109, PMID:26001724, PMID:33542532, PMID:27030050).

Mechanistic history

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

    Established that PLA2G6 encodes a functional calcium-independent phospholipase A2 existing as two splice isoforms with distinct ATP regulation, defining the enzyme's basic biochemistry.

    Evidence cDNA cloning from human pancreatic islets, recombinant expression, in vitro phospholipase assays with BEL inhibition

    PMID:10092647

    Open questions at the time
    • Physiological substrate selectivity in vivo not yet defined
    • Functional significance of ATP activation of long isoform unresolved
  2. 2006 Medium

    Linked PLA2G6 loss-of-function to infantile neuroaxonal dystrophy, establishing the enzyme as essential for neuronal membrane homeostasis in humans.

    Evidence Homozygosity mapping and mutational analysis in INAD patients with neuropathological correlation

    PMID:17033970

    Open questions at the time
    • No in vitro enzymatic reconstitution of mutants in this study
    • Molecular pathway from enzyme loss to axonal spheroids not defined
  3. 2009 High

    Demonstrated that the ankyrin repeat domain is required for catalytic activity and that abolished activity drives INAD pathology, mapping structure to function and disease.

    Evidence ENU mutagenesis mouse model with biochemical enzyme assay and ultrastructural neuropathology

    PMID:19893029

    Open questions at the time
    • Mechanism by which ankyrin domain supports catalysis unresolved
    • Link between activity loss and tubulovesicular membrane formation indirect
  4. 2010 High

    Resolved that INAD/NBIA mutations cause near-complete activity loss whereas parkinsonism mutations spare or increase activity, establishing distinct enzymatic mechanisms for the two disease spectra.

    Evidence Purified recombinant wildtype/mutant proteins assayed against phospholipid and lysophospholipid substrates

    PMID:20886109 PMID:21700586 PMID:23182313

    Open questions at the time
    • Why activity-preserving mutations cause parkinsonism not explained by general phospholipase activity
    • Substrate-specific defects not assayed in this work
  5. 2010 High

    Showed iPLA2β selectively liberates DHA from brain phospholipids in vivo, defining a specific lipid-signaling substrate relevant to neuronal function.

    Evidence Knockout mice with [14C]DHA tracer autoradiography across brain regions; corticostriatal LTP electrophysiology with DHA rescue

    PMID:20686114 PMID:25562715

    Open questions at the time
    • Mechanistic link from DHA release to synaptic plasticity not fully defined
    • Inhibitor used for LTP studies is non-selective
  6. 2008 High

    Identified a non-phospholipase fatty acyl-CoA thioesterase activity of iPLA2β contributing to fatty acid oxidation, broadening its enzymatic repertoire.

    Evidence Knockout mouse skeletal muscle with affinity-purified enzyme, palmitate oxidation and thioesterase assays

    PMID:18937505

    Open questions at the time
    • Relative physiological weight of thioesterase vs phospholipase activity unclear
    • Tissue specificity beyond muscle not established
  7. 2008 High

    Defined iPLA2β as a stimulus-selective signaling enzyme coupling specific agonists and receptors to arachidonic-acid/lysophospholipid mediator production and directional cell behavior.

    Evidence Pharmacological/antisense/knockout approaches across smooth muscle, monocytes, and U937 cells with eicosanoid, migration, and Ca2+ readouts

    PMID:12089145 PMID:15007079 PMID:17613534 PMID:18156193 PMID:18208975

    Open questions at the time
    • Mechanism of agonist-specific iPLA2β recruitment unresolved
    • Some studies rely on non-selective BEL inhibition
  8. 2008 High

    Established that under ER stress iPLA2β translocates to ER/mitochondria and drives a ceramide–mitochondrial-permeability-transition–caspase apoptotic axis, positioning it in stress-induced cell death.

    Evidence Overexpression and BEL inhibition in INS-1 cells with subcellular fractionation, ceramide and mitochondrial membrane potential measurements, caspase/cytochrome c assays

    PMID:14744135 PMID:18936091

    Open questions at the time
    • Mechanism of iPLA2β translocation to mitochondria not defined
    • Link between lipid hydrolysis and ceramide generation indirect
  9. 2013 High

    Placed iPLA2β upstream of p38 MAPK and showed it controls insulin secretion and Bcl-x splicing, integrating its lipid mediators into β-cell signaling and survival decisions.

    Evidence Overexpression/knockout islet and INS-1 systems with p38 inhibitor epistasis, secretion assays, and RT-PCR splice variant quantification with lipid treatment

    PMID:11278673 PMID:22194610 PMID:25762722

    Open questions at the time
    • How a lipid metabolite controls splice-site selection mechanistically unresolved
    • Direct vs indirect activation of p38 by arachidonic acid not separated
  10. 2016 High

    Genetic mouse models established that PLA2G6 deficiency causes age-dependent dopaminergic neurodegeneration with autophagic/Ca2+ dysfunction, ER stress, mitochondrial damage, and α-synuclein/Lewy body accumulation, linking enzyme loss to parkinsonian pathology.

    Evidence Exon2 and D331Y knockin/knockout mice plus patient tissue with neuronal counting, Ca2+/autophagy assays, EM, ER stress markers, and α-synuclein immunohistochemistry

    PMID:25950622 PMID:26755131 PMID:27030050 PMID:28213071 PMID:30088174

    Open questions at the time
    • Causal ordering of mitochondrial damage vs α-synuclein accumulation correlative
    • Direct molecular trigger of dopaminergic vulnerability unresolved
  11. 2018 High

    Revealed that iPLA2β maintains phospholipid acyl-chain length and binds retromer (Vps35/Vps26) to promote membrane recycling and prevent ceramide-driven lysosomal/ER stress, providing a membrane-homeostasis mechanism for neurodegeneration.

    Evidence Drosophila iPLA2-VIA loss-of-function with Co-IP, brain lipidomics, ER-stress markers, transgenic rescue with wildtype vs mutant human protein, and lipid/ceramide-modulating rescue

    PMID:29909971 PMID:31548400

    Open questions at the time
    • Reciprocal validation and direct interface of retromer binding not detailed
    • Relationship between recycling defect and catalytic activity unresolved
  12. 2021 High

    Identified hydrolysis of the ferroptotic signal 15-HpETE-PE as a key protective activity, defining a GPX4-independent ferroptosis-suppressing function whose selective loss causes Parkinson's disease.

    Evidence Purified-enzyme peroxidase assays, GPX4-null cells, patient fibroblasts, CRISPR R748W knockin mice, multiple PD models, and xenograft tumor studies with ferroptosis endpoints

    PMID:33087576 PMID:33542532 PMID:34131139

    Open questions at the time
    • Structural basis for selective peroxidized-lipid recognition not defined
    • Connection between ferroptosis suppression and earlier mitochondrial/α-synuclein phenotypes not unified
  13. 2021 Medium

    Showed iPLA2β translocates to the ER during myocardial ischemia/reperfusion to promote ER-stress apoptosis, extending its stress-apoptotic role beyond β-cells.

    Evidence Knockout and siRNA approaches in vivo and in cells with biotinylation/immunofluorescence ER localization and apoptosis readouts

    PMID:34207793

    Open questions at the time
    • Single lab; signal triggering ER translocation unknown
    • Relationship to ceramide axis in heart not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single enzyme reconciles its protective peroxidized-lipid-detoxifying role with its pro-apoptotic ER/mitochondrial functions, and what determines context-specific outcomes, remains unresolved.
  • No structural model linking substrate selectivity to disease-specific mutant phenotypes
  • Mechanism of regulated subcellular translocation across contexts unknown
  • Unified pathway from enzyme loss to dopaminergic neurodegeneration not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 7 GO:0008289 lipid binding 3 GO:0140098 catalytic activity, acting on RNA 3 GO:0016740 transferase activity 1
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005634 nucleus 2 GO:0005739 mitochondrion 2 GO:0005768 endosome 1 GO:0005794 Golgi apparatus 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-5357801 Programmed Cell Death 6 R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-1430728 Metabolism 2 R-HSA-5653656 Vesicle-mediated transport 1
Partners
VPS26VPS35
Complex memberships
retromer (Vps35/Vps26)

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 PLA2G6 encodes a calcium-independent phospholipase A2 (iPLA2β) that catalyzes hydrolysis of glycerophospholipids; loss-of-function mutations in PLA2G6 cause infantile neuroaxonal dystrophy (INAD), establishing the enzyme's essential role in neuronal membrane homeostasis. Homozygosity mapping, mutational analysis, and identification of PLA2G6 mutations in INAD patients; corroborated by neuropathological findings of axonal spheroids American journal of human genetics Medium 17033970
1999 Human PLA2G6 (iPLA2β) gene on chromosome 22q13.1 produces two catalytically active isoforms (85 kDa and 88 kDa) via exon-skipping alternative splicing; the long isoform (LH-iPLA2) is activated by ATP whereas the short isoform (SH-iPLA2) is not, demonstrating isoform-specific regulatory differences. cDNA cloning from human pancreatic islets, recombinant protein expression, in vitro phospholipase assays with bromoenol lactone inhibition, chromosomal mapping The Journal of biological chemistry High 10092647
2002 iPLA2β (PLA2G6), but not iPLA2γ, is the primary mediator of arginine vasopressin-induced arachidonic acid release from A-10 smooth muscle cells; established using enantioselective inhibition showing (S)-BEL selectively inhibits iPLA2β (IC50 ~2 µM) while (R)-BEL preferentially inhibits iPLA2γ. Chiral HPLC separation of BEL enantiomers, pharmacological inhibition in intact cells, arachidonic acid release assay The Journal of biological chemistry High 12089145
2001 iPLA2β overexpression in INS-1 insulinoma cells amplifies glucose- and cAMP-stimulated insulin secretion without affecting arachidonic acid incorporation into phosphatidylcholine, indicating a signaling rather than housekeeping (phospholipid remodeling) role; cAMP-elevating agents cause perinuclear accumulation of iPLA2β. Stable retroviral overexpression in INS-1 cells, insulin secretion assays, ESI-MS lipid analysis, immunocytofluorescence The Journal of biological chemistry High 11278673
2004 iPLA2β mediates ER stress-induced apoptosis in insulin-secreting INS-1 cells; overexpression amplifies thapsigargin-induced apoptosis and ceramide accumulation, inhibition suppresses it, and ER stress triggers caspase-3-catalyzed cleavage of 84 kDa iPLA2β to a 62 kDa product that associates with nuclei. iPLA2β overexpression in INS-1 cells, BEL pharmacological inhibition, flow cytometry for apoptosis, ceramide measurement, immunofluorescence Biochemistry High 14744135
2007 iPLA2β (PLA2G6) plays a pivotal role in angiotensin II-induced RGS2 mRNA upregulation in vascular smooth muscle cells; demonstrated by three independent approaches (BEL inhibition, antisense oligonucleotides, iPLA2β-null mice); Ang II stimulates iPLA2 enzymatic activity in VSMC; downstream products arachidonic acid and lysophosphatidylcholine induce RGS2 via lipoxygenase pathway. Pharmacological inhibition (BEL), antisense oligonucleotide knockdown, iPLA2β knockout mice, adenovirus-mediated gene rescue, iPLA2 enzymatic activity assays, real-time PCR The Journal of biological chemistry High 17613534
2008 Upon MCP-1 stimulation, iPLA2β translocates to the membrane-enriched pseudopod in monocytes and controls directionality and actin polymerization during chemotaxis; antisense knockdown of iPLA2β reduces migration speed, directionality, and abolishes in vivo peritoneal migration. Antisense oligonucleotide knockdown, immunofluorescence localization, in vitro chemotaxis assays, adoptive transfer in vivo migration assay The Journal of experimental medicine High 18208975
2008 iPLA2β mediates ER stress-induced apoptosis via a ceramide-mitochondria axis: ER stress promotes iPLA2β accumulation in mitochondria, ceramide generation via sphingomyelin hydrolysis, mitochondrial permeability transition pore opening, loss of mitochondrial membrane potential, cytochrome c/Smac release, and caspase-3 activation; these are amplified by iPLA2β overexpression and inhibited by iPLA2β inactivation or NSMase inhibition. iPLA2β overexpressing INS-1 cells (OE), BEL inhibition, subcellular fractionation, ceramide measurement in ER and mitochondria fractions, mitochondrial membrane potential assay, cytochrome c/Smac immunoblotting The Journal of biological chemistry High 18936091
2007 iPLA2β-dependent activation of store-operated Ca2+ channels (SOC) is required for agonist-induced Ca2+ influx and vasoconstriction in cerebral, mesenteric, and carotid arteries; iPLA2β inhibition abolishes phenylephrine-induced Ca2+ entry without affecting K+-induced (voltage-gated L-type channel-dependent) vasoconstriction. Pharmacological inhibition of iPLA2β (BEL) in intact pressurized vessels, simultaneous measurement of intracellular Ca2+ and vessel diameter American journal of physiology. Heart and circulatory physiology Medium 18156193
2009 A point mutation in the ankyrin repeat domain of Pla2g6 completely abolishes glycerophospholipid-catalyzing enzyme activity while allowing protein expression, demonstrating that the ankyrin repeat domain is required for catalytic function and that loss of iPLA2β enzymatic activity causes INAD neuropathology. ENU mutagenesis mouse model, biochemical enzyme activity assay on mutant protein, neuropathological examination (axonal spheroids with tubulovesicular membranes) The American journal of pathology High 19893029
2010 PLA2G6 mutations associated with INAD/NBIA cause loss of enzyme activity (<20% residual activity for both phospholipase and lysophospholipase substrates), while mutations associated with dystonia-parkinsonism do not impair catalytic activity and two mutations increase specific activity for phospholipid substrates, indicating distinct disease mechanisms. Purified recombinant wildtype and mutant human PLA2G6 proteins, in vitro phospholipase and lysophospholipase assays with radiolabeled lipid substrates PloS one High 20886109
2010 iPLA2β deficiency in mice reduces brain DHA metabolism and signaling both at baseline and following muscarinic receptor activation, consistent with iPLA2β selectively hydrolyzing DHA from phospholipids in vivo. iPLA2β knockout mice, quantitative autoradiography with [1-14C]DHA intravenous infusion, measurement of DHA incorporation coefficients in 81 brain regions Journal of lipid research High 20686114
2011 Homozygous PLA2G6 D331Y mutation causes ~70% reduction in iPLA2β enzyme activity in vitro, linking reduced catalytic activity to autosomal recessive early-onset parkinsonism. Direct sequencing for mutation identification, in vitro enzyme activity assay of D331Y mutant vs. wildtype PLA2G6 Neurology Medium 21700586
2011 iPLA2β is activated upstream of p38 MAPK in pancreatic β-cells: glucose and thapsigargin stimulate p38 MAPK phosphorylation in an iPLA2β-dependent manner; p38 MAPK inhibition prevents insulin secretion and apoptosis downstream of iPLA2β; iPLA2β product arachidonic acid activates p38 MAPK. iPLA2β overexpressing INS-1 cells and knockout mice islets, BEL pharmacological inhibition, p38 MAPK inhibitor PD169316, phosphorylation immunoblotting, insulin secretion assay, apoptosis assay The Journal of biological chemistry High 22194610
2012 Three PLA2G6 frameshift and missense mutations found in PD patients reduce iPLA2β phospholipase activity (P.His597fx69: <6% residual activity; Leu656Val: 55% residual; Leu693Val: 65% residual), extending the genotype-activity relationship in PD-associated PLA2G6 mutations. Sequencing in patient cohort, in vitro phospholipase assay with recombinant mutant proteins Parkinsonism & related disorders Medium 23182313
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 were confirmed in fibroblasts from human PLA2G6 mutation patients; deuterated PUFAs (inhibiting lipid peroxidation) partially rescued locomotor deficits and restored mitochondrial membrane potential. Drosophila iPLA2-VIA knockout, mitochondrial respiratory chain assays, ATP measurement, electron microscopy, lipid peroxidation assays; patient-derived fibroblast studies; deuterated PUFA rescue experiment Brain : a journal of neurology High 26001724
2016 PLA2G6-dependent Ca2+ signaling activates store-operated Ca2+ entry (SOCE); genetic or molecular impairment of PLA2g6-dependent Ca2+ signaling in a PLA2g6 exon2 knockout mouse triggers autophagic dysfunction and progressive loss of dopaminergic neurons in substantia nigra pars compacta with age-dependent L-DOPA-sensitive motor dysfunction. PLA2g6 exon2 knockout mouse model, Ca2+ signaling measurements, autophagy assays, dopaminergic neuron counting, behavioral motor tests Nature communications High 26755131
2018 iPLA2-VIA (Drosophila PLA2G6 homolog) binds retromer subunits Vps35 and Vps26 and enhances retromer function to promote protein and lipid recycling; loss of iPLA2-VIA does not alter phospholipid composition but causes elevation of ceramides leading to lysosomal stress and neurodegeneration; reducing ceramides with myriocin or desipramine alleviates neurodegeneration. Co-immunoprecipitation/pulldown of iPLA2-VIA with Vps35/Vps26, lipidomics of fly brain tissue, pharmacological ceramide reduction (myriocin, desipramine), Drosophila genetic loss-of-function Cell metabolism High 29909971
2019 Loss of iPLA2-VIA in Drosophila shortens acyl-chain length of phospholipids, causing ER stress through membrane lipid disequilibrium; wild-type human iPLA2-VIA or the mitochondria-ER contact site protein C19orf12 rescues lipid composition, ER stress, and DA neurodegeneration, while disease-associated A80T mutant fails to rescue; linoleic acid supplementation corrects brain lipid composition and suppresses α-synuclein aggregation. iPLA2-VIA-deficient Drosophila, lipid mass spectrometry of brain tissue, ER stress markers, transgenic rescue with wildtype vs. mutant human iPLA2-VIA, linoleic acid supplementation, α-synuclein aggregation assay Proceedings of the National Academy of Sciences of the United States of America High 31548400
2020 PLA2G6 (iPLA2β) hydrolyzes ferroptotic death signal 15-HpETE-PE (hydroperoxy-arachidonoyl-phosphatidylethanolamine) in placental trophoblasts, attenuating ferroptosis induced by GPX4 inhibition or hypoxia/reoxygenation injury in vivo. Primary human trophoblast cell culture, mouse pregnancy model, GPX4 inhibition, lipid peroxidation assays, in vitro and in vivo ferroptosis endpoints Proceedings of the National Academy of Sciences of the United States of America High 33087576
2021 iPLA2β hydrolyzes 15-HpETE-PE (generated by 15-LOX/PEBP1 complexes) to avert ferroptosis; genetic or pharmacological inactivation sensitizes cells to ferroptosis; a PD-associated patient mutation (R747W) selectively reduces 15-HpETE-PE-hydrolyzing activity, causes 15-HpETE-PE accumulation, and elevates ferroptosis sensitivity; CRISPR-Cas9 Pnpla9R748W/R748W mice develop progressive parkinsonian motor deficits with 15-HpETE-PE accumulation. Biochemical lipid peroxidase assay with purified iPLA2β, patient-derived fibroblasts (fPDR747W), CRISPR-Cas9 knockin mice, lipidomics (15-HpETE-PE quantification), motor behavior tests, rotenone rat model, SncaA53T mice Nature chemical biology High 33542532
2021 iPLA2β suppresses p53-driven ferroptosis upon ROS-induced stress by detoxifying peroxidized lipids, even in GPX4-null cells; inhibition of endogenous iPLA2β sensitizes tumor cells to p53-driven ferroptosis and promotes p53-dependent tumor suppression in xenograft models; loss of iPLA2β has no obvious effect on normal cell viability. GPX4-null cell lines, iPLA2β inhibition and overexpression, ROS-induced stress assays, ferroptosis cell death assays, xenograft mouse tumor models Nature communications High 34131139
2015 PLA2G6 loss-of-function causes Golgi morphology disruption and defects in protein O-linked glycosylation and sialylation in patient-derived fibroblasts; these defects are rescued by lentiviral overexpression of wild-type PLA2G6, establishing PLA2G6 as required for normal Golgi function. Patient-derived fibroblasts, HPLC and MALDI-TOF/MS glycosylation analysis, immunofluorescence for Golgi morphology, lentiviral wildtype PLA2G6 rescue Journal of medical genetics Medium 26668131
2015 In PLA2G6 knockout mice, mitochondria with damaged inner membranes appear early before symptom onset and move anterogradely into distal axons; inner mitochondrial membrane collapse accompanies axonal injury near impaired mitochondria; presynaptic membranes expand and rupture causing axon terminal degeneration; both processes generate tubulovesicular structures, the ultrastructural marker of INAD. PLA2G6 knockout mouse neuropathological analysis, electron microscopy, axonal transport studies Neuropathology : official journal of the Japanese Society of Neuropathology Medium 25950622
2016 In PLA2G6-knockout mouse neurons, elevated α-synuclein/phosphorylated α-synuclein expression occurs early in mitochondria with degenerated inner membranes (TOM20-positive granules); in PLAN patient neurons, phospho-α-synuclein-positive inclusions with TOM20-positive edges cluster into Lewy bodies, suggesting PLA2G6 deficiency-induced mitochondrial damage drives α-synuclein accumulation and Lewy body formation. PLA2G6 knockout mouse brain immunohistochemistry, iPLA2β knockdown cell lines, human PLAN brain tissue immunohistochemistry, electron microscopy, quantitative neuronal analysis Acta neuropathologica communications Medium 27030050
2017 PLA2G6 protein accumulates in the cores of brainstem-type Lewy bodies in both PARK14 and idiopathic Parkinson's disease patients but not in cortical Lewy bodies or other synucleinopathies, establishing a physical association between PLA2G6 and Lewy body pathology. Immunohistochemistry and Western blotting of human brain tissue from PARK14, idiopathic PD, DLB, MSA, and normal controls using anti-PLA2G6 antibodies Neuroscience letters Medium 28213071
2018 PARK14 (D331Y) PLA2G6 knockin mice develop early-onset death of substantia nigra dopaminergic neurons with disrupted mitochondrial cristae, mitochondrial dysfunction, elevated ROS, ER stress (elevated GRP78, IRE1, PERK, CHOP), mitophagy impairment (reduced Parkin and BNIP3), and transcriptional dysregulation; Lewy body pathology was found in substantia nigra. Knockin mouse model (PLA2G6D331Y/D331Y), dopaminergic neuron counting, electron microscopy of mitochondria, mitochondrial function assays, ER stress marker immunoblotting, motor behavior tests Molecular neurobiology High 30088174
2012 iPLA2β in smooth muscle cells participates in vascular inflammation and neointima formation; smooth muscle-specific iPLA2β transgenic mice show exacerbated ligation-induced neointima with enhanced cytokine production and macrophage infiltration; Ang II-, arachidonic acid-, and TNF-α-induced IL-6/TNF-α expression in VSMC is suppressed by iPLA2β inhibition/deletion; downstream 12/15-lipoxygenase pathway mediates these effects. iPLA2β knockout and smooth muscle-specific transgenic mice, carotid artery ligation model, BEL pharmacological inhibition, antisense oligonucleotides, cultured VSMC with cytokine assays, 12/15-lipoxygenase genetic/pharmacological inhibition The Journal of biological chemistry High 22637477
2007 iPLA2 associated with endosomal and exosomal membranes in reticulocytes is activated by reactive oxygen species produced during 15-lipoxygenase-induced mitochondria degeneration, leading to lysophosphatidylcholine generation on exosome surfaces that enables IgM antibody binding and complement-mediated clearance. Reticulocyte maturation model, subcellular fractionation (endosomal/exosomal), ROS measurement, lipid analysis, IgM binding assay, C3 deposition detection Blood Medium 17666570
2008 iPLA2β mediates FcγRI-triggered arachidonic acid release and leukotriene B4/prostaglandin E2 generation in human monocytic cells (U937); this is protein kinase C-dependent, whereas platelet-activating factor activates cPLA2α through MAPK, demonstrating selective coupling of different stimuli to distinct PLA2 isoforms. BEL pharmacological inhibition, selective receptor agonists, eicosanoid measurement, PKC inhibitor studies in U937 cells The Journal of biological chemistry Medium 15007079
2008 iPLA2β exhibits thioesterase activity that hydrolyzes fatty acyl-CoAs; skeletal muscle from iPLA2β-null mice shows reduced acyl-CoA thioesterase activity and reduced capacity to oxidize palmitate (but not palmitoyl-CoA or acetyl-CoA), revealing a novel function distinct from phospholipase activity that contributes to fatty acid oxidation. iPLA2β-null mouse skeletal muscle, sequential ATP/calmodulin affinity chromatography, palmitate oxidation assay, acyl-CoA thioesterase activity assay, BEL inhibition Biochemistry High 18937505
2015 iPLA2β inhibition blocks corticostriatal long-term potentiation (LTP) and depotentiation; acute application of docosahexaenoic acid (DHA) restores LTP after iPLA2β inhibition, indicating iPLA2β-mediated DHA release is required for corticostriatal synaptic plasticity. Acute BEL application to rat brain slices, field potential electrophysiology, DHA rescue experiment Brain research bulletin Medium 25562715
2015 iPLA2β modulates Bcl-x pre-mRNA 5' splice site selection in β-cells; ER stress shifts splicing toward pro-apoptotic Bcl-x(S) in an iPLA2β-dependent manner; iPLA2β inactivation or knockout increases anti-apoptotic Bcl-x(L)/Bcl-x(S) ratio; 5(S)-HETE (a lipoxygenase metabolite of arachidonic acid) augments Bcl-x(L)/Bcl-x(S) ratio 15.5-fold, identifying a lipid mediator mechanism. Chemical inactivation, knockdown, RIP-iPLA2β transgenic and iPLA2β knockout mouse islets, RT-PCR splice variant quantification, exogenous lipid treatment The Journal of biological chemistry High 25762722
2021 iPLA2β expression increases during myocardial ischemia/reperfusion injury and the protein translocates to the ER upon I/R; iPLA2β knockout mice and siRNA knockdown reduce ER stress and cardiomyocyte apoptosis during I/R injury, demonstrating iPLA2β promotes ER stress-induced apoptosis by translocating to ER. iPLA2β knockout mice, siRNA knockdown, in vivo mouse I/R model, cell surface protein biotinylation, immunofluorescence localization to ER, 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 352 18570303
2021 iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4. Nature communications 296 34131139
2021 Phospholipase iPLA2β averts ferroptosis by eliminating a redox lipid death signal. Nature chemical biology 287 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
2020 PLA2G6 guards placental trophoblasts against ferroptotic injury. Proceedings of the National Academy of Sciences of the United States of America 170 33087576
2010 Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations. Neurobiology of aging 168 20619503
2015 Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction. Brain : a journal of neurology 161 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 156 12089145
2006 PLA2G6 mutation underlies infantile neuroaxonal dystrophy. American journal of human genetics 147 17033970
2018 Phospholipase PLA2G6, a Parkinsonism-Associated Gene, Affects Vps26 and Vps35, Retromer Function, and Ceramide Levels, Similar to α-Synuclein Gain. Cell metabolism 146 29909971
2010 Phenotypic spectrum of patients with PLA2G6 mutation and PARK14-linked parkinsonism. Neurology 120 20938027
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 96 18826942
2010 The roles of iPLA2, TRPM8 and TRPA1 in chemically induced cold hypersensitivity. Molecular pain 95 20092626
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 90 14744135
2018 PLA2G6-Associated Neurodegeneration (PLAN): Review of Clinical Phenotypes and Genotypes. Frontiers in neurology 86 30619057
2011 PLA2G6 gene mutation in autosomal recessive early-onset parkinsonism in a Chinese cohort. Neurology 86 21700586
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 82 31548400
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 82 18936091
2016 Impairment of PARK14-dependent Ca(2+) signalling is a novel determinant of Parkinson's disease. Nature communications 81 26755131
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
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 PRDX6 promotes lung tumor progression via its GPx and iPLA2 activities. Free radical biology & medicine 67 24512906
2008 iPLA2beta: front and center in human monocyte chemotaxis to MCP-1. The Journal of experimental medicine 66 18208975
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 62 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
2007 Reticulocyte-secreted exosomes bind natural IgM antibodies: involvement of a ROS-activatable endosomal phospholipase iPLA2. Blood 53 17666570
2008 Clinical study and PLA2G6 mutation screening analysis in Chinese patients with infantile neuroaxonal dystrophy. European journal of neurology 50 19138334
2010 Imaging decreased brain docosahexaenoic acid metabolism and signaling in iPLA(2)β (VIA)-deficient mice. Journal of lipid research 49 20686114
2017 Dysfunction of PLA2G6 and CYP2C44-associated network signals imminent carcinogenesis from chronic inflammation to hepatocellular carcinoma. Journal of molecular cell biology 48 28655161
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
2017 PARK14 PLA2G6 mutants are defective in preventing rotenone-induced mitochondrial dysfunction, ROS generation and activation of mitochondrial apoptotic pathway. Oncotarget 47 29108286
2012 Four novel rare mutations of PLA2G6 in Chinese population with Parkinson's disease. Parkinsonism & related disorders 47 23182313
2015 Neuroaxonal dystrophy in PLA2G6 knockout mice. Neuropathology : official journal of the Japanese Society of Neuropathology 46 25950622
2016 High expression of α-synuclein in damaged mitochondria with PLA2G6 dysfunction. Acta neuropathologica communications 45 27030050
2007 Role of iPLA2 and store-operated channels in agonist-induced Ca2+ influx and constriction in cerebral, mesenteric, and carotid arteries. American journal of physiology. Heart and circulatory physiology 44 18156193
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 43 30088174
2014 Inhibition of Ca2+-independent phospholipase A2β (iPLA2β) ameliorates islet infiltration and incidence of diabetes in NOD mice. Diabetes 43 25213337
2013 New findings in a global approach to dissect the whole phenotype of PLA2G6 gene mutations. PloS one 43 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
2020 Genotype-phenotype correlations of adult-onset PLA2G6-associated Neurodegeneration: case series and literature review. BMC neurology 40 32183746
2017 PLA2G6 mutations associated with a continuous clinical spectrum from neuroaxonal dystrophy to hereditary spastic paraplegia. Clinical genetics 40 28295203
2010 Group VIA Ca2+-independent phospholipase A2 (iPLA2beta) and its role in beta-cell programmed cell death. Biochimie 40 20083151
2022 Vitamin E prevents lipid peroxidation and iron accumulation in PLA2G6-Associated Neurodegeneration. Neurobiology of disease 39 35122944
2016 iPLA2β deficiency attenuates obesity and hepatic steatosis in ob/ob mice through hepatic fatty-acyl phospholipid remodeling. Biochimica et biophysica acta 39 26873633
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
2018 PLA2G6-associated neurodegeneration: New insights into brain abnormalities and disease progression. Parkinsonism & related disorders 38 30340910
2013 Extensive aggregation of α-synuclein and tau in juvenile-onset neuroaxonal dystrophy: an autopsied individual with a novel mutation in the PLA2G6 gene-splicing site. Acta neuropathologica communications 38 24252552
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
2005 Identification and distribution of endoplasmic reticulum iPLA2. Biochemical and biophysical research communications 37 15629460
2011 Genetic ablation of PLA2G6 in mice leads to cerebellar atrophy characterized by Purkinje cell loss and glial cell activation. PloS one 36 22046428
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
2020 Azoramide protects iPSC-derived dopaminergic neurons with PLA2G6 D331Y mutation through restoring ER function and CREB signaling. Cell death & disease 33 32071291
2018 iPLA2β and its role in male fertility, neurological disorders, metabolic disorders, and inflammation. Biochimica et biophysica acta. Molecular and cell biology of lipids 32 30408523
2017 PLA2G6 accumulates in Lewy bodies in PARK14 and idiopathic Parkinson's disease. Neuroscience letters 32 28213071
2011 The PLA2G6 gene in early-onset Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society 32 21812034
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
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 31 23977134
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
2015 Disruption of Golgi morphology and altered protein glycosylation in PLA2G6-associated neurodegeneration. Journal of medical genetics 30 26668131
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
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
2014 Loss of presenilin 2 is associated with increased iPLA2 activity and lung tumor development. Oncogene 29 24858037
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 28 23411472
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 26 25004092
2010 iPLA2, a novel determinant in Ca2+- and phosphorylation-dependent S100A8/A9 regulated NOX2 activity. Biochimica et biophysica acta 26 20219570
2023 The role of the PLA2G6 gene in neurodegenerative diseases. Ageing research reviews 25 37236368
2018 Mutations in the Drosophila homolog of human PLA2G6 give rise to age-dependent loss of psychomotor activity and neurodegeneration. Scientific reports 25 29440694
2018 Heterozygous PLA2G6 Mutation Leads to Iron Accumulation Within Basal Ganglia and Parkinson's Disease. Frontiers in neurology 25 30042723
2024 PRDX6-iPLA2 aggravates neuroinflammation after ischemic stroke via regulating astrocytes-induced M1 microglia. Cell communication and signaling : CCS 24 38287382
2017 Alteration of mitochondrial protein PDHA1 in Lewy body disease and PARK14. Biochemical and biophysical research communications 24 28564592
2005 iPLA2 inhibitor blocks negative inotropic effect of HIV gp120 on cardiac myocytes. Journal of molecular and cellular cardiology 24 16316660
2001 Role of calcium-independent phospholipases (iPLA(2)) in phosphatidylcholine metabolism. Biochemical and biophysical research communications 24 11563837
2014 Urocortin affects migration of hepatic cancer cell lines via differential regulation of cPLA2 and iPLA2. Cellular signalling 23 24518041
2011 Group VIA PLA2 (iPLA2β) is activated upstream of p38 mitogen-activated protein kinase (MAPK) in pancreatic islet β-cell signaling. The Journal of biological chemistry 23 22194610
2019 Early-Onset Parkinson's Disease Caused by PLA2G6 Compound Heterozygous Mutation, a Case Report and Literature Review. Frontiers in neurology 22 31496990
2018 PLA2G6-associated neurodegeneration presenting as a complicated form of hereditary spastic paraplegia. Journal of human genetics 22 30302010
2016 Validation of the finding of hypertrophy of the clava in infantile neuroaxonal dystrophy/PLA2G6 by biometric analysis. Neuroradiology 22 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
2018 Pla2g6 Deficiency in Zebrafish Leads to Dopaminergic Cell Death, Axonal Degeneration, Increased β-Synuclein Expression, and Defects in Brain Functions and Pathways. Molecular neurobiology 20 29344929
2018 Novel PLA2G6 mutations and clinical heterogeneity in Chinese cases with phospholipase A2-associated neurodegeneration. Parkinsonism & related disorders 20 29454663
2016 Mutation screening of PLA2G6 in Japanese patients with early onset dystonia-parkinsonism. Journal of neural transmission (Vienna, Austria : 1996) 19 27942883
2014 iPLA2β knockout mouse, a genetic model for progressive human motor disorders, develops age-related neuropathology. Neurochemical research 19 24919816
2021 iPLA2β Contributes to ER Stress-Induced Apoptosis during Myocardial Ischemia/Reperfusion Injury. Cells 18 34207793
2019 iPla2β deficiency in mice fed with MCD diet does not correct the defect of phospholipid remodeling but attenuates hepatocellular injury via an inhibition of lipid uptake genes. Biochimica et biophysica acta. Molecular and cell biology of lipids 18 30735854
2012 Smooth muscle-specific expression of calcium-independent phospholipase A2β (iPLA2β) participates in the initiation and early progression of vascular inflammation and neointima formation. The Journal of biological chemistry 18 22637477
2020 PLA2G6 variants associated with the number of affected alleles in Parkinson's disease in Japan. Neurobiology of aging 17 32771225
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

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