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Dayan B Goodenowe - One of the best experts on this subject based on the ideXlab platform.
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Plasmalogen augmentation reverses striatal dopamine loss in mptp mice
PLOS ONE, 2016Co-Authors: Edith Mivillegodbout, Tara C Smith, Dushmanthi Jayasinghe, Melanie Bourque, Marc Morissette, Sara Alsweidi, Asuka Mochizuki, Vijitha Senanayake, Li Wang, Dayan B GoodenoweAbstract:Plasmalogens are a class of glycerophospholipids shown to play critical roles in membrane structure and function. Decreased Plasmalogens are reported in the brain and blood of Parkinson’s disease (PD) patients. The present study investigated the hypothesis that augmenting Plasmalogens could protect striatal dopamine neurons that degenerate in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in mice, a PD model. First, in a pre-treatment experiment male mice were treated for 10 days with the docosahexaenoic acid (DHA)-Plasmalogen precursor PPI-1011 (10, 50 and 200 mg/kg). On day 5 mice received MPTP and were killed on day 11. Next, in a post-treatment study, male mice were treated with MPTP and then received daily for 5 days PPI-1011 (5, 10 and 50 mg/kg). MPTP treatment reduced serum Plasmalogen levels, striatal contents of dopamine (DA) and its metabolites, serotonin, DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2). Pre-treatment with PPI-1011 (10 and 50 mg/kg) prevented all MPTP-induced effects. Positive correlations were measured between striatal DA contents and serum Plasmalogen levels as well as striatal DAT and VMAT2 specific binding. Post-treatment with PPI-1011 prevented all MPTP-induced effects at 50 mg/kg but not at lower doses. Positive correlations were measured between striatal DA contents and serum Plasmalogen levels as well as striatal DAT and VMAT2 specific binding in the post-treatment experiment. PPI-1011 treatment (10 days at 5, 10 and 50 mg/kg) of intact mice left unchanged striatal biogenic amine contents. These data demonstrate that treatment with a Plasmalogen precursor is capable of protecting striatal dopamine markers in an animal model of PD.
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oral bioavailability of the ether lipid Plasmalogen precursor ppi 1011 in the rabbit a new therapeutic strategy for alzheimer s disease
Lipids in Health and Disease, 2011Co-Authors: Paul L Wood, Amin M Khan, Tara C Smith, Greg Ehrmantraut, Nina Lane, Dayan B GoodenoweAbstract:Introduction Docosahexaenoic acid (DHA) and DHA-containing ethanolamine Plasmalogens (PlsEtn) are decreased in the brain, liver and the circulation in Alzheimer's disease. Decreased supply of Plasmalogen precursors to the brain by the liver, as a result of peroxisomal deficits is a process that probably starts early in the AD disease process. To overcome this metabolic compromise, we have designed an orally bioavailable DHA-containing ether lipid precursor of Plasmalogens. PPI-1011 is an alkyl-diacyl Plasmalogen precursor with palmitic acid at sn-1, DHA at sn-2 and lipoic acid at sn-3. This study outlines the oral pharmacokinetics of this precursor and its conversion to PlsEtn and phosphatidylethanolamines (PtdEtn).
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in vitro and in vivo Plasmalogen replacement evaluations in rhizomelic chrondrodysplasia punctata and pelizaeus merzbacher disease using ppi 1011 an ether lipid Plasmalogen precursor
Lipids in Health and Disease, 2011Co-Authors: Paul L Wood, Amin M Khan, Tara C Smith, Greg Ehrmantraut, Nancy Braverman, Dayan B GoodenoweAbstract:Background Childhood peroxisomal disorders and leukodystrophies are devastating diseases characterized by dysfunctional lipid metabolism. Plasmalogens (ether glycerophosphoethanolamine lipids) are decreased in these genetic disorders. The biosynthesis of Plasmalogens is initiated in peroxisomes but completed in the endoplasmic reticulum. We therefore undertook a study to evaluate the ability of a 3-substituted, 1-alkyl, 2-acyl glyceryl ether lipid (PPI-1011) to replace Plasmalogens in rhizomelic chrondrodysplasia punctata type 1 (RCDP1) and rhizomelic chrondrodysplasia punctata type 2 (RCDP2) lymphocytes which possess peroxisomal mutations culminating in deficient Plasmalogen synthesis. We also examined Plasmalogen synthesis in Pelizaeus-Merzbacher disease (PMD) lymphocytes which possess a proteolipid protein-1 (PLP1) missense mutation that results in abnormal PLP1 folding and it's accumulation in the endoplasmic reticulum (ER), the cellular site of the last steps in Plasmalogen synthesis. In vivo incorporation of Plasmalogen precursor into tissue Plasmalogens was also evaluated in the Pex7 mouse model of Plasmalogen deficiency.
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membrane Plasmalogen composition and cellular cholesterol regulation a structure activity study
Lipids in Health and Disease, 2010Co-Authors: Rishikesh Mankidy, Paul L Wood, Dushmanthi Jayasinghe, Shawn Ritchie, Pearson W K Ahiahonu, Mohamed A Khan, Khine Khine Sumyat, Dayan B GoodenoweAbstract:Background Disrupted cholesterol regulation leading to increased circulating and membrane cholesterol levels is implicated in many age-related chronic diseases such as cardiovascular disease (CVD), Alzheimer's disease (AD), and cancer. In vitro and ex vivo cellular Plasmalogen deficiency models have been shown to exhibit impaired intra- and extra-cellular processing of cholesterol. Furthermore, depleted brain Plasmalogens have been implicated in AD and serum Plasmalogen deficiencies have been linked to AD, CVD, and cancer.
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circulating Plasmalogen levels and alzheimer disease assessment scale cognitive scores in alzheimer patients
Journal of Psychiatry & Neuroscience, 2010Co-Authors: Paul L Wood, Shawn Ritchie, Rishikesh Mankidy, Doug Heath, Julie A Wood, John Flax, Dayan B GoodenoweAbstract:Background: Plasmalogens, which are key structural phospholipids in brain membranes, are decreased in the brain and serum of patients with Alzheimer disease (AD). We performed this pilot study to evaluate the relation between the levels of circulating Plasmalogens and Alzheimer Disease Assessment Scale–Cognitive (ADAS-Cog) scores in patients with AD. Methods: We evaluated participants’ ADAS-Cog scores and serum Plasmalogen levels. For the 40 included AD patients with an ADAS-Cog score between 20 and 46, we retested their ADAS-Cog score 1 year later. The levels of docosahexaenoic acid Plasmalogen were measured by use of liquid chromatography–tandem mass spectrometry. Results: We found that the ADAS-Cog score increased significantly in AD patients with circulating Plasmalogen levels that were ≤ 75% of that of age-matched controls at entry into the study. There was no change in score among participants with normal serum Plasmalogen levels at baseline (> 75%). Limitations: This was a pilot study with 40 patients, and the results require validation in a larger population. Conclusion: Our study demonstrates that decreased levels of Plasmalogen precursors in the central nervous system correlate with functional decline (as measured by ADAS-Cog scores) in AD patients. The use of both ADAS-Cog and serum Plasmalogen data may be a more accurate way of predicting cognitive decline in AD patients, and may be used to decrease the risk of including patients with no cognitive decline in the placebo arm of a drug trial.
Raphael A Zoeller - One of the best experts on this subject based on the ideXlab platform.
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on the importance of Plasmalogen status in stimulated arachidonic acid release in the macrophage cell line raw 264 7
Biochimica et Biophysica Acta, 2008Co-Authors: Daniel P Gaposchkin, Harrison W Farber, Raphael A ZoellerAbstract:Abstract We examined the dependence of stimulated arachidonic acid release on Plasmalogens using the murine, macrophage cell line 264.7 and two Plasmalogen-deficient variants, RAW.12 and RAW.108. All three strains responded to unopsinized zymosan to release arachidonic acid from phospholipid stores. Arachidonic acid release appeared to be dependent on calcium-independent phospholipase A2 activation (iPLA2); bromoenol lactone, a specific inhibitor of calcium-independent iPLA2, blocked arachidonic acid release with an IC50 of approximately 2 × 10− 7M. Propanolol, an inhibitor of phosphatidate phosphatase, and RHC-80267, an inhibitor of diglyceride lipase, had no effect on arachidonic acid release. Arachidonic acid release in the variants displayed similar magnitude, kinetics of response and sensitivity to the inhibitors when compared to the parent strain. Arachidonic acid was released from all major phospholipid head group classes with the exception of sphingomyelin. In wild-type cells, arachidonic acid released from the ethanolamine phospholipids was primarily from the Plasmalogen form. However, in the Plasmalogen-deficient cells release from the diacyl species, phosphatidylethanolamine, was increased to compensate. Restoration of Plasmalogens by supplementation of the growth medium with the bypass compounds sn-1-hexadecylglycerol and sn-1-alkenylglycerol had no effect on arachidonic acid release. In summary, Plasmalogen status appears to have no influence on the zymosan A stimulated release of arachidonic acid from the RAW 264.7 cell line.
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Role of dihydroxyacetonephosphate acyltransferase in the biosynthesis of Plasmalogens and nonether glycerolipids.
Journal of Lipid Research, 2005Co-Authors: Narasimhan Nagan, Wilhelm W. Just, Claus Rodemer, Thanh-phuong Thai, Raphael A ZoellerAbstract:The variant CHO-K1 cell line, NRel-4, is unable to synthesize Plasmalogens because of a severe reduction in dihydroxyacetonephosphate acyltransferase (DHAPAT) activity (Nagan, N., A. K. Hajra, L. K. Larkins, P. Lazarow, P. E. Purdue, W. B. Rizzo, and R. A. Zoeller. 1998. Isolation of a Chinese hamster fibroblast variant defective in dihydroxyacetonephosphate acyltransferase activity and Plasmalogen biosynthesis: use of a novel two-step selection protocol. Biochem. J. 332: 273-279). Northern analysis demonstrated that the loss of this activity was attributable to a severe reduction in mRNA levels for DHAPAT. Transfection of NRel-4 cells with a plasmid bearing the human DHAPAT cDNA recovered DHAPAT activity and Plasmalogen biosynthesis. Examination of clonal isolates from the transfected population showed that recovery of as little as 10% of wild-type DHAPAT activity restored Plasmalogen levels to 55% of normal, whereas in one isolate, NRel-4.15, which overexpressed DHAPAT activity by 6-fold over wild-type cells, Plasmalogen levels were returned only to wild-type values. Although the rate of plasmenylethanolamine biosynthesis was restored in NRel-4.15, the biosynthesis of nonether glycerolipids was either decreased or unaffected, suggesting that peroxisomal DHAPAT does not normally contribute to nonether glycerolipid biosynthesis. These data demonstrate that a defect in the gene that codes for peroxisomal DHAPAT is the primary lesion in the NRel-4 cell line and that the peroxisomal DHAPAT is essential for the biosynthesis of Plasmalogens in animal cells.
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deficiency in ethanolamine Plasmalogen leads to altered cholesterol transport
Journal of Lipid Research, 2003Co-Authors: Natalie J Munn, Raphael A Zoeller, Emily Arnio, Laura LiscumAbstract:Plasmalogens are a major sub-class of ethanolamine and choline phospholipids in which the sn -1 position has a long chain fatty alcohol attached through a vinyl ether bond. These phospholipids are proposed to play a role in membrane fusion-mediated events. In this study, we investi- gated the role of the ethanolamine Plasmalogen plasmenyl- ethanolamine (PlsEtn) in intracellular cholesterol transport in Chinese hamster ovary cell mutants NRel-4 and NZel-1, which have single gene defects in PlsEtn biosynthesis. We found that PlsEtn was essential for specific cholesterol transport path- ways, those from the cell surface or endocytic compart- ments to acyl-CoA/cholesterol acyltransferase in the endo- plasmic reticulum. The movement of cholesterol from the endoplasmic reticulum or endocytic compartments to the cell surface was normal in PlsEtn-deficient cells. Also, vesicle trafficking was normal in PlsEtn-deficient cells, as measured by fluid phase endocytosis and exocytosis, as was the move- ment of newly-synthesized proteins to the cell surface. The mutant cholesterol transport phenotype was due to the lack of PlsEtn, since it was corrected when NRel-4 cells were transfected with a cDNA encoding the missing enzyme or supplied with a metabolic intermediate that enters the PlsEtn biosynthetic pathway downstream of the defect. Fu- ture work must determine the precise role that Plasmalogens have on cholesterol transport to the endoplasmic reticulum.— Munn, N. J., E. Arnio, D. Liu, R. A. Zoeller, and L. Liscum. Deficiency in ethanolamine Plasmalogen leads to altered cholesterol transport. J. Lipid Res. 2003. 44: 182-192.
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Plasmalogen status influences docosahexaenoic acid levels in a macrophage cell line insights using ether lipid deficient variants
Journal of Lipid Research, 1999Co-Authors: Daniel P Gaposchkin, Raphael A ZoellerAbstract:Previously, this laboratory reported the isolation of variants, RAW.12 and RAW.108, from the macrophage- like cell line RAW 264.7 that are defective in Plasmalogen biosynthesis ( Zoeller, R.A. et al. 1992. J. Biol. Chem. 267: 8299-8306). Fatty acid analysis showed significant changes in the mutants in the ethanolamine phospholipids (PE), the only phospholipid class in which the Plasmalogen species, plasmenylethanolamine, contributes significantly. Within the PE fraction, docosapentaenoic (DPA; 22:5n-3) and docosahexaenoic (DHA; 22:6n-3) acids were reduced by ap- proximately 50% in the variants while the levels of arachi- donic acid (AA; 20:4n-6) remained unaffected. The de- crease in DHA was accompanied by a 50% decrease in labeling PE with ( 3 H)DHA over a 90-min period. Restora- tion of plasmenylethanolamine by supplementing the growth medium with sn -1-hexadecylglycerol (HG) completely re- versed these changes in RAW.108. Pre-existing pools of plasmenylethanolamine were not required for restoration of normal ( 3 H)DHA labeling; addition of HG only during the labeling period was sufficient. Due to the loss of D 1 9 - desaturase in RAW.12, HG supplementation resulted in the accumulation of plasmenylethanolamine's immediate bio- synthetic precursor, plasmanylethanolamine. Even though this latter phospholipid contained only the ether functional- ity (lacking the vinyl ether double bond) it was sufficient to restore wild type-like fatty acid composition and DHA label- ing of the ethanolamine phospholipids, identifying the ether bond as a structural determinant for this specificity. In summary, we have used these mutants to establish that the Plasmalogen status of a cell can influence the levels of certain polyunsaturated fatty acids. These results support the notion that certain polyunsaturated fatty acids, such as DHA, can be selectively targeted to Plasmalogens and that this targeting occurs during de novo biosynthesis, or shortly thereafter, through modification of nascent Plasmalogen pools. —Gaposchkin, D. P., and R. A. Zoeller. Plasmalogen status influences docosahexaenoic acid levels in a macroph- age cell line: insights using ether lipid-deficient variants. J. Lipid Res. 1999. 40: 495-503.
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isolation of a chinese hamster fibroblast variant defective in dihydroxyacetonephosphate acyltransferase activity and Plasmalogen biosynthesis use of a novel two step selection protocol
Biochemical Journal, 1998Co-Authors: Narasimhan Nagan, Amiya K Hajra, Paul B Lazarow, Edward P Purdue, Leslie K Larkins, William B Rizzo, Raphael A ZoellerAbstract:We have developed a two-step selection protocol to generate a population of Chinese hamster ovary (CHO) cell variants that are Plasmalogen-deficient, but contain intact, functional peroxisomes (Plasmalogen-/peroxisome+). This involved sequential exposures of a mutagenized cell population to photodynamic damage by using two different pyrene-labelled sensors, 9-(1´-pyrene)nonanol and 12-(1´-pyrene)dodecanoic acid. By this procedure we generated several isolates, all except one of which displayed a severe decrease in Plasmalogen biosynthesis. Further characterization of one of the Plasmalogen-deficient isolates, NRel-4, showed that it contained intact, functional peroxisomes. Whole-cell homogenates from NRel-4 displayed severely decreased dihydroxyacetone phosphate acyltransferase, which catalyses the first step in Plasmalogen biosynthesis. NRel-4 and another, recently described, Plasmalogen-deficient cell line, NZel-1 [Nagan, Hajra, Das, Moser, Moser, Lazarow, Purdue and Zoeller (1997) Proc. Natl. Acad. Sci. U.S.A. 94 , 4475–4480] were hypersensitive to singlet oxygen, supporting the notion of Plasmalogens as radical oxygen scavengers. Wild-type-like resistance could be conferred on NRel-4 upon restoration of Plasmalogen content by supplementation with a bypass compound, sn -1-hexadecylglycerol. NRel-4 and other Plasmalogen-/peroxisome+ strains will allow us to examine further the role of ether lipids in cellular functions without complications associated with peroxisome deficiency, and might serve as an animal cell model for certain forms of the human genetic disorder rhizomelic chondrodysplasia punctata.
Paul L Wood - One of the best experts on this subject based on the ideXlab platform.
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dysfunctional Plasmalogen dynamics in the plasma and platelets of patients with schizophrenia
Schizophrenia Research, 2015Co-Authors: Paul L Wood, Greg Unfried, Willard Whitehead, Aaron Phillipps, Julie A WoodAbstract:Abstract Background Based upon the concept of a prodromal risk syndrome for first psychosis, intense efforts are being applied to define potential biomarkers of disease onset in schizophrenia. One such tentative biomarker may be Plasmalogens, complex structural glycerophospholipids that serve multiple functions in all cells. Methods To further investigate this possibility, we undertook a lipidomics analysis of choline and ethanolamine Plasmalogens in the plasma and platelets of 23 patients with schizophrenia and 27 age-matched controls. Results Plasma levels of both choline and ethanolamine Plasmalogens were decreased by 23 to 45% in patients with schizophrenia. In platelets, from patients with schizophrenia, ethanolamine Plasmalogens also were decreased while choline Plasmalogen levels were increased. Levels of docosahexaenoic acid (DHA) were decreased by approximately 30% both in plasma and platelets. Conclusions Our results suggest that alterations in lipid transport or lipid remodeling/metabolism of Plasmalogens are present in schizophrenia and that changes in the steady-state levels of these complex lipid pools may be involved in altered neuronal function.
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Dysfunctional Plasmalogen dynamics in the plasma and platelets of patients with schizophrenia.
Schizophrenia research, 2014Co-Authors: Paul L Wood, Greg Unfried, Willard Whitehead, Aaron Phillipps, Julie A WoodAbstract:Based upon the concept of a prodromal risk syndrome for first psychosis, intense efforts are being applied to define potential biomarkers of disease onset in schizophrenia. One such tentative biomarker may be Plasmalogens, complex structural glycerophospholipids that serve multiple functions in all cells. To further investigate this possibility, we undertook a lipidomics analysis of choline and ethanolamine Plasmalogens in the plasma and platelets of 23 patients with schizophrenia and 27 age-matched controls. Plasma levels of both choline and ethanolamine Plasmalogens were decreased by 23 to 45% in patients with schizophrenia. In platelets, from patients with schizophrenia, ethanolamine Plasmalogens also were decreased while choline Plasmalogen levels were increased. Levels of docosahexaenoic acid (DHA) were decreased by approximately 30% both in plasma and platelets. Our results suggest that alterations in lipid transport or lipid remodeling/metabolism of Plasmalogens are present in schizophrenia and that changes in the steady-state levels of these complex lipid pools may be involved in altered neuronal function. Copyright © 2014 Elsevier B.V. All rights reserved.
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oral bioavailability of the ether lipid Plasmalogen precursor ppi 1011 in the rabbit a new therapeutic strategy for alzheimer s disease
Lipids in Health and Disease, 2011Co-Authors: Paul L Wood, Amin M Khan, Tara C Smith, Greg Ehrmantraut, Nina Lane, Dayan B GoodenoweAbstract:Introduction Docosahexaenoic acid (DHA) and DHA-containing ethanolamine Plasmalogens (PlsEtn) are decreased in the brain, liver and the circulation in Alzheimer's disease. Decreased supply of Plasmalogen precursors to the brain by the liver, as a result of peroxisomal deficits is a process that probably starts early in the AD disease process. To overcome this metabolic compromise, we have designed an orally bioavailable DHA-containing ether lipid precursor of Plasmalogens. PPI-1011 is an alkyl-diacyl Plasmalogen precursor with palmitic acid at sn-1, DHA at sn-2 and lipoic acid at sn-3. This study outlines the oral pharmacokinetics of this precursor and its conversion to PlsEtn and phosphatidylethanolamines (PtdEtn).
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in vitro and in vivo Plasmalogen replacement evaluations in rhizomelic chrondrodysplasia punctata and pelizaeus merzbacher disease using ppi 1011 an ether lipid Plasmalogen precursor
Lipids in Health and Disease, 2011Co-Authors: Paul L Wood, Amin M Khan, Tara C Smith, Greg Ehrmantraut, Nancy Braverman, Dayan B GoodenoweAbstract:Background Childhood peroxisomal disorders and leukodystrophies are devastating diseases characterized by dysfunctional lipid metabolism. Plasmalogens (ether glycerophosphoethanolamine lipids) are decreased in these genetic disorders. The biosynthesis of Plasmalogens is initiated in peroxisomes but completed in the endoplasmic reticulum. We therefore undertook a study to evaluate the ability of a 3-substituted, 1-alkyl, 2-acyl glyceryl ether lipid (PPI-1011) to replace Plasmalogens in rhizomelic chrondrodysplasia punctata type 1 (RCDP1) and rhizomelic chrondrodysplasia punctata type 2 (RCDP2) lymphocytes which possess peroxisomal mutations culminating in deficient Plasmalogen synthesis. We also examined Plasmalogen synthesis in Pelizaeus-Merzbacher disease (PMD) lymphocytes which possess a proteolipid protein-1 (PLP1) missense mutation that results in abnormal PLP1 folding and it's accumulation in the endoplasmic reticulum (ER), the cellular site of the last steps in Plasmalogen synthesis. In vivo incorporation of Plasmalogen precursor into tissue Plasmalogens was also evaluated in the Pex7 mouse model of Plasmalogen deficiency.
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membrane Plasmalogen composition and cellular cholesterol regulation a structure activity study
Lipids in Health and Disease, 2010Co-Authors: Rishikesh Mankidy, Paul L Wood, Dushmanthi Jayasinghe, Shawn Ritchie, Pearson W K Ahiahonu, Mohamed A Khan, Khine Khine Sumyat, Dayan B GoodenoweAbstract:Background Disrupted cholesterol regulation leading to increased circulating and membrane cholesterol levels is implicated in many age-related chronic diseases such as cardiovascular disease (CVD), Alzheimer's disease (AD), and cancer. In vitro and ex vivo cellular Plasmalogen deficiency models have been shown to exhibit impaired intra- and extra-cellular processing of cholesterol. Furthermore, depleted brain Plasmalogens have been implicated in AD and serum Plasmalogen deficiencies have been linked to AD, CVD, and cancer.
Yukio Fujiki - One of the best experts on this subject based on the ideXlab platform.
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Plasmalogen homeostasis regulation of Plasmalogen biosynthesis and its physiological consequence in mammals
FEBS Letters, 2017Co-Authors: Masanori Honsho, Yukio FujikiAbstract:Plasmalogens, mostly ethanolamine-containing alkenyl ether phospholipids, are a major subclass of glycerophospholipids. Plasmalogen synthesis is initiated in peroxisomes and completed in the endoplasmic reticulum. The absence of Plasmalogens in several organs of peroxisome biogenesis-defective patients suggests that the de novo synthesis of Plasmalogens plays a pivotal role in its homeostasis in tissues. Plasmalogen synthesis is regulated by modulating the stability of fatty acyl-CoA reductase 1 on peroxisomal membranes, a rate-limiting enzyme in Plasmalogen synthesis, by sensing Plasmalogens in the inner leaflet of plasma membranes. Dysregulation of Plasmalogen homeostasis impairs cholesterol biosynthesis by altering the stability of squalene monooxygenase, a key enzyme in cholesterol biosynthesis, implying physiological consequences of Plasmalogen homeostasis with respect to cholesterol metabolism in cells, as well as in organs such as the liver.
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Plasmalogen homeostasis – regulation of Plasmalogen biosynthesis and its physiological consequence in mammals
FEBS Letters, 2017Co-Authors: Masanori Honsho, Yukio FujikiAbstract:Plasmalogens, mostly ethanolamine-containing alkenyl ether phospholipids, are a major subclass of glycerophospholipids. Plasmalogen synthesis is initiated in peroxisomes and completed in the endoplasmic reticulum. The absence of Plasmalogens in several organs of peroxisome biogenesis-defective patients suggests that the de novo synthesis of Plasmalogens plays a pivotal role in its homeostasis in tissues. Plasmalogen synthesis is regulated by modulating the stability of fatty acyl-CoA reductase 1 on peroxisomal membranes, a rate-limiting enzyme in Plasmalogen synthesis, by sensing Plasmalogens in the inner leaflet of plasma membranes. Dysregulation of Plasmalogen homeostasis impairs cholesterol biosynthesis by altering the stability of squalene monooxygenase, a key enzyme in cholesterol biosynthesis, implying physiological consequences of Plasmalogen homeostasis with respect to cholesterol metabolism in cells, as well as in organs such as the liver.
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Plasmalogen biosynthesis is spatiotemporally regulated by sensing Plasmalogens in the inner leaflet of plasma membranes
Scientific Reports, 2017Co-Authors: Masanori Honsho, Yukio FujikiAbstract:Alkenyl ether phospholipids are a major sub-class of ethanolamine- and choline-phospholipids in which a long chain fatty alcohol is attached at the sn-1 position through a vinyl ether bond. Biosynthesis of ethanolamine-containing alkenyl ether phospholipids, Plasmalogens, is regulated by modulating the stability of fatty acyl-CoA reductase 1 (Far1) in a manner dependent on the level of cellular Plasmalogens. However, precise molecular mechanisms underlying the regulation of Plasmalogen synthesis remain poorly understood. Here we show that degradation of Far1 is accelerated by inhibiting dynamin-, Src kinase-, or flotillin-1-mediated endocytosis without increasing the cellular level of Plasmalogens. By contrast, Far1 is stabilized by sequestering cholesterol with nystatin. Moreover, abrogation of the asymmetric distribution of Plasmalogens in the plasma membrane by reducing the expression of CDC50A encoding a β-subunit of flippase elevates the expression level of Far1 and Plasmalogen synthesis without reducing the total cellular level of Plasmalogens. Together, these results support a model that Plasmalogens localised in the inner leaflet of the plasma membranes are sensed for Plasmalogen homeostasis in cells, thereby suggesting that Plasmalogen synthesis is spatiotemporally regulated by monitoring cellular level of Plasmalogens.
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analysis of Plasmalogen synthesis in cultured cells
Methods of Molecular Biology, 2017Co-Authors: Masanori Honsho, Yukio FujikiAbstract:Plasmalogen synthesis can be analyzed by metabolic labeling, followed by the separation of ethanolamine Plasmalogens from glycerophospholipids on one-dimensional thin-layer chromatography. The vinyl-ether bond of Plasmalogens is acid-labile, which allows separating Plasmalogens as 2-acyl-glycerophospholipids from diacyl-glycerophospholipids.
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dysregulation of Plasmalogen homeostasis impairs cholesterol biosynthesis
Journal of Biological Chemistry, 2015Co-Authors: Masanori Honsho, Yukio FujikiAbstract:Plasmalogen biosynthesis is regulated by modulating fatty acyl-CoA reductase 1 stability in a manner dependent on cellular Plasmalogen level. However, physiological significance of the regulation of Plasmalogen biosynthesis remains unknown. Here we show that elevation of the cellular Plasmalogen level reduces cholesterol biosynthesis without affecting the isoprenylation of proteins such as Rab and Pex19p. Analysis of intermediate metabolites in cholesterol biosynthesis suggests that the first oxidative step in cholesterol biosynthesis catalyzed by squalene monooxygenase (SQLE), an important regulator downstream HMG-CoA reductase in cholesterol synthesis, is reduced by degradation of SQLE upon elevation of cellular Plasmalogen level. By contrast, the defect of Plasmalogen synthesis causes elevation of SQLE expression, resulting in the reduction of 2,3-epoxysqualene required for cholesterol synthesis, hence implying a novel physiological consequence of the regulation of Plasmalogen biosynthesis.
Tara C Smith - One of the best experts on this subject based on the ideXlab platform.
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Plasmalogen precursor mitigates striatal dopamine loss in mptp mice
Brain Research, 2017Co-Authors: Edith Mivillegodbout, Tara C Smith, Dushmanthi Jayasinghe, Shawn Ritchie, Melanie Bourque, Marc Morissette, Sara Alsweidi, Therese Di PaoloAbstract:Abstract Ethanolamine Plasmalogens (PlsEtn) are a class of glycerophospholipids characterized by a vinyl-ether bond at the sn-1 position that play an important role in the structure and function of membranes. Previous reports have suggested a link between reduced blood and brain PlsEtn levels and Parkinson’s disease (PD). We recently reported that the DHA containing Plasmalogen precursor PPI-1011 protected striatal dopamine (DA) against MPTP toxicity in mice. In this paper, we further investigate the specificity requirements of the lipid side chains by testing the oleic acid-containing Plasmalogen precursor PPI-1025. Male mice were treated for 10 days with daily oral administration of PPI-1025 (10, 50 or 200 mg/kg). On day 5 mice received MPTP and were sacrificed on Day 11. Treatment with PPI-1025 prevented MPTP-induced decrease of DA and serotonin, as well as their metabolites. In addition, PPI-1025 treatment prevented the MPTP-induced decrease of the striatal dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) specific binding. Significant positive correlations were measured between striatal DA concentrations and DAT or VMAT2 specific binding, as well as with serum Plasmalogen concentrations. The neuroprotective effect of PPI-1025 displayed a bell-curve dose-dependency losing effect at the highest dose tested. The similar protective response of oleic and docosahexaenoic acid (DHA)-containing Plasmalogen precursors suggests that the neuroprotection observed is not only due to DHA but to the oleic substituent and the Plasmalogen backbone.
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Plasmalogen augmentation reverses striatal dopamine loss in mptp mice
PLOS ONE, 2016Co-Authors: Edith Mivillegodbout, Tara C Smith, Dushmanthi Jayasinghe, Melanie Bourque, Marc Morissette, Sara Alsweidi, Asuka Mochizuki, Vijitha Senanayake, Li Wang, Dayan B GoodenoweAbstract:Plasmalogens are a class of glycerophospholipids shown to play critical roles in membrane structure and function. Decreased Plasmalogens are reported in the brain and blood of Parkinson’s disease (PD) patients. The present study investigated the hypothesis that augmenting Plasmalogens could protect striatal dopamine neurons that degenerate in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in mice, a PD model. First, in a pre-treatment experiment male mice were treated for 10 days with the docosahexaenoic acid (DHA)-Plasmalogen precursor PPI-1011 (10, 50 and 200 mg/kg). On day 5 mice received MPTP and were killed on day 11. Next, in a post-treatment study, male mice were treated with MPTP and then received daily for 5 days PPI-1011 (5, 10 and 50 mg/kg). MPTP treatment reduced serum Plasmalogen levels, striatal contents of dopamine (DA) and its metabolites, serotonin, DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2). Pre-treatment with PPI-1011 (10 and 50 mg/kg) prevented all MPTP-induced effects. Positive correlations were measured between striatal DA contents and serum Plasmalogen levels as well as striatal DAT and VMAT2 specific binding. Post-treatment with PPI-1011 prevented all MPTP-induced effects at 50 mg/kg but not at lower doses. Positive correlations were measured between striatal DA contents and serum Plasmalogen levels as well as striatal DAT and VMAT2 specific binding in the post-treatment experiment. PPI-1011 treatment (10 days at 5, 10 and 50 mg/kg) of intact mice left unchanged striatal biogenic amine contents. These data demonstrate that treatment with a Plasmalogen precursor is capable of protecting striatal dopamine markers in an animal model of PD.
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oral bioavailability of the ether lipid Plasmalogen precursor ppi 1011 in the rabbit a new therapeutic strategy for alzheimer s disease
Lipids in Health and Disease, 2011Co-Authors: Paul L Wood, Amin M Khan, Tara C Smith, Greg Ehrmantraut, Nina Lane, Dayan B GoodenoweAbstract:Introduction Docosahexaenoic acid (DHA) and DHA-containing ethanolamine Plasmalogens (PlsEtn) are decreased in the brain, liver and the circulation in Alzheimer's disease. Decreased supply of Plasmalogen precursors to the brain by the liver, as a result of peroxisomal deficits is a process that probably starts early in the AD disease process. To overcome this metabolic compromise, we have designed an orally bioavailable DHA-containing ether lipid precursor of Plasmalogens. PPI-1011 is an alkyl-diacyl Plasmalogen precursor with palmitic acid at sn-1, DHA at sn-2 and lipoic acid at sn-3. This study outlines the oral pharmacokinetics of this precursor and its conversion to PlsEtn and phosphatidylethanolamines (PtdEtn).
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in vitro and in vivo Plasmalogen replacement evaluations in rhizomelic chrondrodysplasia punctata and pelizaeus merzbacher disease using ppi 1011 an ether lipid Plasmalogen precursor
Lipids in Health and Disease, 2011Co-Authors: Paul L Wood, Amin M Khan, Tara C Smith, Greg Ehrmantraut, Nancy Braverman, Dayan B GoodenoweAbstract:Background Childhood peroxisomal disorders and leukodystrophies are devastating diseases characterized by dysfunctional lipid metabolism. Plasmalogens (ether glycerophosphoethanolamine lipids) are decreased in these genetic disorders. The biosynthesis of Plasmalogens is initiated in peroxisomes but completed in the endoplasmic reticulum. We therefore undertook a study to evaluate the ability of a 3-substituted, 1-alkyl, 2-acyl glyceryl ether lipid (PPI-1011) to replace Plasmalogens in rhizomelic chrondrodysplasia punctata type 1 (RCDP1) and rhizomelic chrondrodysplasia punctata type 2 (RCDP2) lymphocytes which possess peroxisomal mutations culminating in deficient Plasmalogen synthesis. We also examined Plasmalogen synthesis in Pelizaeus-Merzbacher disease (PMD) lymphocytes which possess a proteolipid protein-1 (PLP1) missense mutation that results in abnormal PLP1 folding and it's accumulation in the endoplasmic reticulum (ER), the cellular site of the last steps in Plasmalogen synthesis. In vivo incorporation of Plasmalogen precursor into tissue Plasmalogens was also evaluated in the Pex7 mouse model of Plasmalogen deficiency.
