Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease

Nelson, Rochelle K.; Frohman, Michael A.

doi:10.1194/jlr.r059220

Cited by 110 publications

(81 citation statements)

References 113 publications

(136 reference statements)

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“…Mammalian phosphatidylcholine cleaving PLD (two isoforms: PLD1 and PLD2) cleaves phosphatidylcholine to phosphatidic acid/choline via phosphodiesterase action, and brain‐associated PLD function can affect membrane curvature, exocytosis, endocytosis, vesicle release, and neurite outgrowth, all of which are important in synaptic function [9]. Our previous studies also implicated PLD isoforms in rodent associative memory mechanisms [11–13].…”

Section: Introductionmentioning

confidence: 96%

Elevated phospholipase D isoform 1 in Alzheimer's disease patients' hippocampus: Relevance to synaptic dysfunction and memory deficits

Krishnan

Kayed

Taglialatela

2018

A&D Transl Res & Clin Interv

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IntroductionPhospholipase D (PLD), a lipolytic enzyme that breaks down membrane phospholipids, is also involved in signaling mechanisms downstream of seven transmembrane receptors. Abnormally elevated levels of PLD activity are well-established in Alzheimer's disease (AD), implicating the two isoforms of mammalian phosphatidylcholine cleaving PLD (PC-PLD1 and PC-PLD2). Therefore, we took a systematic approach of investigating isoform-specific expression in human synaptosomes and further investigated the possibility of therapeutic intervention using preclinical studies.MethodsSynaptosomal Western blot analyses on the postmortem human hippocampus, temporal cortex, and frontal cortex of AD patient brains/age-matched controls and the 3XTg-AD mice hippocampus (mouse model with overexpression of human amyloid precursor protein, presenilin-1 gene, and microtubule-associated protein tau causing neuropathology progressing comparable to that in human AD patients) were used to detect the levels of neuronal PLD1 expression. Mouse hippocampal long-term potentiation of PLD1-dependent changes was studied using pharmacological approaches in ex vivo slice preparations from wild-type and transgenic mouse models. Finally, PLD1-dependent changes in novel object recognition memory were assessed following PLD1 inhibition.ResultsWe observed elevated synaptosomal PLD1 in the hippocampus/temporal cortex from postmortem tissues of AD patients compared to age-matched controls and age-dependent hippocampal PLD1 increases in 3XTg-AD mice. PLD1 inhibition blocked effects of oligomeric amyloid β or toxic oligomeric tau species on high-frequency stimulation long-term potentiation and novel object recognition deficits in wild-type mice. Finally, PLD1 inhibition blocked long-term potentiation deficits normally observed in aging 3XTg-AD mice.DiscussionUsing human studies, we propose a novel role for PLD1-dependent signaling as a critical mechanism underlying oligomer-driven synaptic dysfunction and consequent memory disruption in AD. We, further, provide the first set of preclinical studies toward future therapeutics targeting PLD1 in slowing down/stopping the progression of AD-related memory deficits as a complementary approach to immunoscavenging clinical trials that are currently in progress.

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Section: Introductionmentioning

confidence: 96%

Elevated phospholipase D isoform 1 in Alzheimer's disease patients' hippocampus: Relevance to synaptic dysfunction and memory deficits

Krishnan

Kayed

Taglialatela

2018

A&D Transl Res & Clin Interv

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“…Another pathway is the acylation of DHAP to 1‐acyl‐DHAP (Ac‐DHAP) via DHAP acyltransferase (DHAP AT), followed by the reduction of Ac‐DHAP to LPA via Ac‐DHAP reductase . the phosphorylation of diacylglycerol (DAG) by diacylglycerol kinases (DGKs) . Ten members of DGK family are known ( and references therein); hydrolysis of phospholipids by phospholipase D (PLD) . Among the six known PLD isoforms, the mammalian PLD1 and PLD2 are the best studied ( and references therein).…”

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confidence: 99%

“…Among the six known PLD isoforms, the mammalian PLD1 and PLD2 are the best studied ( and references therein). PLD6 (MitoPLD) generates PA via hydrolysis of cardiolipin on the outer surface of the mitochondria . At present, no enzymatic activity has been reported for PLD5 and for the two Endoplasmic Reticulum‐localized PLD isoforms, namely PLD3 and PLD4 .…”

mentioning

confidence: 99%

Phosphatidic acid in membrane rearrangements

et al. 2019

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Phosphatidic acid (PA) is the simplest cellular glycerophospholipid characterized by unique biophysical properties: a small headgroup; negative charge; and a phosphomonoester group. Upon interaction with lysine or arginine, PA charge increases from −1 to −2 and this change stabilizes protein–lipid interactions. The biochemical properties of PA also allow interactions with lipids in several subcellular compartments. Based on this feature, PA is involved in the regulation and amplification of many cellular signalling pathways and functions, as well as in membrane rearrangements. Thereby, PA can influence membrane fusion and fission through four main mechanisms: it is a substrate for enzymes producing lipids (lysophosphatidic acid and diacylglycerol) that are involved in fission or fusion; it contributes to membrane rearrangements by generating negative membrane curvature; it interacts with proteins required for membrane fusion and fission; and it activates enzymes whose products are involved in membrane rearrangements. Here, we discuss the biophysical properties of PA in the context of the above four roles of PA in membrane fusion and fission.

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“…Phosphohydrolases that cleave phospholipids on the polar or distal side of the phosphodiester bond are called phospholipase D (PLD), and are reviewed by Michael Frohman and his colleague at the State University of New York in Stony Brook in their article " Physiological and pathophysiological roles for phospholipase D " ( 16 ). Gordon Mills and colleagues at the MD Anderson Cancer Center at the University of Texas in Houston have reviewed those PLD enzymes acting on lysophospholipids in their paper titled " Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression " ( 17 ).…”

Section: Phospholipase Focusmentioning

confidence: 99%

Introduction to Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease

Dennis

2015

Journal of Lipid Research

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Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease

Cited by 110 publications

References 113 publications

Elevated phospholipase D isoform 1 in Alzheimer's disease patients' hippocampus: Relevance to synaptic dysfunction and memory deficits

Elevated phospholipase D isoform 1 in Alzheimer's disease patients' hippocampus: Relevance to synaptic dysfunction and memory deficits

Phosphatidic acid in membrane rearrangements

Introduction to Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease

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