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11562447 ( ) |
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| Title | Inhibition of acetylcholine synthesis and tyrosine nitration induced by peroxynitrite are differentially prevented by antioxidants. |
| Abstract | Evidence of an overload of reactive oxygen species and peroxynitrite, a derivative of nitric oxide, in sporadic amyotrophic lateral sclerosis suggests that peroxynitrite could impair cholinergic functions. Because of the impossibility of obtaining synaptosomes from vertebrate neuromuscular junctions, we used cholinergic synaptosomes purified from Torpedo marmorata electroneurons to characterize the defects triggered by peroxynitrite in more detail. Addition of peroxynitrite or its donor 3-morpholinosydnonimine abolished high-affinity choline uptake and synthesis of acetylcholine from acetate. T. marmorata choline acetyltransferase (ChAT) was impaired to the same extent as bovine brain ChAT. A hallmark of peroxynitrite action is the nitration of tyrosine residues in proteins. Peroxynitrite induced a concentration-dependent appearance of nitrotyrosines in several neuronal proteins from synaptosomes and, more readily, from synaptic vesicles. Peroxynitrite also triggered tyrosine nitrations in purified ChAT. Peroxynitrite-dependent nitrations were impaired when synaptosomes were pretreated with thioreductants (glutathione, N-acetyl cysteine, dithiothreitol) or antioxidants (uric acid, melatonin, bovine serum albumin, desferrioxamine). Deleterious effects of peroxynitrite on choline transport and ChAT activity were prevented by the thioreductants but only partially by the antioxidants, suggesting a mechanism other than tyrosine nitration, which may involve cysteine oxidation. Further development of protective agents acting on choline transport and on ChAT activity may offer interesting therapeutic possibilities with respect to cholinergic dysfunction occurring in neurodegenerative diseases. la Recherche Scientifique, Gif-sur-Yvette, France. |
NOTE: Color highlight is limited to the abstract and SciMiner text-mining mode. If you see much more identified targets below from "Targets by SciMiner Summary" and "Targets by SciMiner Full list", they may have been identified from the full text.
Targets by SciMiner Summary
| HUGO ID | Symbol | Target Name | #Occur | ActualStr |
|---|---|---|---|---|
| 11506 | SYP | synaptophysin | 7 | synaptophysin | |
| 1912 | CHAT | choline acetyltransferase | 3 | choline acetyltransferase | |
| 20374 | GSX1 | GS homeobox 1 | 3 | gsh 1 | |
| 399 | ALB | albumin | 3 | serum albumin | |
| 12008 | TPH1 | tryptophan hydroxylase 1 (tryptophan 5-monooxygenase) | 2 | tryptophan hydroxylase | |
| 15814 | ACSS2 | acyl-CoA synthetase short-chain family member 2 | 1 | acetyl coa synthetase | |
| 11782 | TH | tyrosine hydroxylase | 1 | tyrosine hydroxylase | |
| 11138 | SNCA | synuclein, alpha (non A4 component of amyloid precursor) | 1 | alpha synuclein | |
| 6876 | MAPK14 | mitogen-activated protein kinase 14 | 1 | p38 | |
| 12805 | XDH | xanthine dehydrogenase | 1 | xanthine oxidase | |
| 7097 | MIF | macrophage migration inhibitory factor (glycosylation-inhibiting factor) | 1 | Gif-sur-Yvette-Cedex | |
| 24190 | CAMK2N1 | calcium/calmodulin-dependent protein kinase II inhibitor 1 | 1 | calcium/calmodulin dependent protein kinase ii | |
| 16014 | CASD1 | CAS1 domain containing 1 | 1 | o acetyltransferase | |
| 12642 | VAMP1 | vesicle-associated membrane protein 1 (synaptobrevin 1) | 1 | synaptobrevin 1 | |
Targets by SciMiner Full list
| HUGO ID | Symbol | Name | ActualStr | Score | FlankingText |
|---|---|---|---|---|---|
| 6876 | MAPK14 | mitogen-activated protein kinase 14 | p38 | 0.3 | Another protein that was affected was synaptophysin/p38 synaptophysin p38 |
| 7097 | MIF | macrophage migration inhibitory factor (glycosylation-inhibiting factor) | Gif-sur-Yvette-Cedex | 0.3 | et Mol_amp_eacute culaire Center National de la Recherche Scientifique 91198 Gif-sur-Yvette-Cedex France |
| 1912 | CHAT | choline acetyltransferase | choline acetyltransferase | 1.0 | t. marmorata choline acetyltransferase chat was impaired to the same extent as bovine brain chat. |
| 399 | ALB | albumin | serum albumin | 1.0 | peroxynitrite dependent nitrations were impaired when synaptosomes were pretreated with thioreductants glutathione n acetyl cysteine dithiothreitol or antioxidants uric acid melatonin bovine serum albumin desferrioxamine . |
| 12805 | XDH | xanthine dehydrogenase | xanthine oxidase | 1.0 | no can then combine with o 2 which is formed at sites of free radical generation beckman et al. 1990 ; pryor and squadrito 1995 such as mitochondria or through enzyme activity e.g. monoamine oxidase xanthine oxidase to form peroxynitrite onoo . |
| 11782 | TH | tyrosine hydroxylase | tyrosine hydroxylase | 1.0 | clinical studies showed that tyrosine hydroxylase the first and rate limiting enzyme in catecholamine biosynthesis that is selectively affected in parkinson's disease is nitrated suggesting that the cause of the pathology may be an onoo overload ara |
| 15814 | ACSS2 | acyl-CoA synthetase short-chain family member 2 | acetyl coa synthetase | 1.0 | the first is acetate which is converted into acetyl coa by acetyl coa synthetase. |
| 1912 | CHAT | choline acetyltransferase | choline acetyltransferase | 1.0 | synthesis of ach from choline and acetyl coa is performed by choline acetyltransferase chat a cytosolic enzyme wu and hersh 1994 . |
| 11506 | SYP | synaptophysin | synaptophysin | 1.0 | onoo dependent changes in several presynaptic proteins chat synaptophysin vamp/synaptobrevin actin tubulin present in t. marmorata synaptosomes and synaptic vesicles were examined and showed examples of nitration of tyrosines and covalent oligomerization. |
| 11506 | SYP | synaptophysin | synaptophysin | 1.0 | polyclonal antibody against t. marmorata synaptophysin and monoclonal antibodies against vamp/synaptobrevin and tubulin were developed and characterized in the laboratory by dr. nicolas morel laboratoire de neurobiologie cellulaire et moleculaire cnrs gi |
| 399 | ALB | albumin | serum albumin | 1.0 | the reaction was started by the addition of the substrates [1 c]acetyl coa 14 microm and choline 2.5 mm in the presence of 250 microm eserine 10 microm bovine serum albumin bsa and 75 mm nacl and stopped after 1 h by dilution with cold sodium phosphate buffer. |
| 11138 | SNCA | synuclein, alpha (non A4 component of amyloid precursor) | alpha synuclein | 1.0 | 1 but neither was inhibited by h 2 o 2 up to 1 mm this study or by similar concentrations of the no donors s nitroso n acetylpenicillamine and sodium nitroprusside morot gaudry talarmain et al. 1997 alpha synuclein by souza et al 2000 or proteolysis may occur requiring further studies. |
| 24190 | CAMK2N1 | calcium/calmodulin-dependent protein kinase II inhibitor 1 | calcium/calmodulin dependent protein kinase ii | 1.0 | olled proteolysis and subcellular localization cytosolic versus membrane bound isoforms and the presence of thiol agents can all modulate the activity of the enzyme posttranslationally oda 1999 alpha calcium/calmodulin dependent protein kinase ii bruce and hersh 1989 ; dobransky et al. 2000 . |
| 12008 | TPH1 | tryptophan hydroxylase 1 (tryptophan 5-monooxygenase) | tryptophan hydroxylase | 1.0 | inactivation by onoo of the enzyme activity by sulfhydryl oxidation was recently shown to be essential for tryptophan hydroxylase another neurotransmitter synthesis enzyme kuhn and geddes 1999 . |
| 11506 | SYP | synaptophysin | synaptophysin | 1.0 | moreover we were able to define affected residues by taking advantage of a specific antibody raised against a well conserved sequence gyqpnygq q of the t. marmorata synaptophysin cowan et al. 1990 . |
| 11506 | SYP | synaptophysin | synaptophysin | 1.0 | can affect numerous proteins at the presynaptic side of a neuromuscular junction in several subcellular compartments; these include choline transporter at the plasma membrane chat in the cytosol and synaptophysin tubulin or actin at the periphery of synaptic vesicles. |
| 12642 | VAMP1 | vesicle-associated membrane protein 1 (synaptobrevin 1) | synaptobrevin 1 | 1.0 | arrows show actin 1/200 c tubulin 1/1000 d synaptophysin 1/2500 e and vamp/synaptobrevin 1/25 a . |
| 11506 | SYP | synaptophysin | synaptophysin | 1.0 | arrows show actin 1/200 c tubulin 1/1000 d synaptophysin 1/2500 e and vamp/synaptobrevin 1/25 a . |
| 20374 | GSX1 | GS homeobox 1 | gsh 1 | 1.0 | concentration of the drugs were as follows: 5 mm gsh 1.25 mm nac 1 mm uric acid 1 mm bsa 1 mm dtt 200 microm desferrioxamine deferriox and 1 mm melatonin. |
| 20374 | GSX1 | GS homeobox 1 | gsh 1 | 1.0 | concentrations of protectors were for the high affinity choline uptake protection assay a : 5 mm gsh 1 mm nac 1 mm dtt 0.5 mm uric acid 1 mm bsa 200 microm desferrioxamine desfer. 1 mm melatonin melat. ; and for chat activity protection assay b : 5 mm gsh 5 mm nac 1 mm dtt 1 mm uric acid 1 mm bsa 200 |
| 11506 | SYP | synaptophysin | synaptophysin | 1.0 | synaptophysin an integral vesicular 38 kda glycoprotein was detected in the controls fig 5 e as a doublet using an antibody directed against the c terminal epitope gyqpnygq q cowan et al. 1990 ; n morel personal c |
| 12008 | TPH1 | tryptophan hydroxylase 1 (tryptophan 5-monooxygenase) | tryptophan hydroxylase | 1.0 | as shown for tryptophan hydroxylase kuhn and geddes 1999 protection against onoo induced tyrosine nitrations may prevent the loss of enzymatic activity. |
| 20374 | GSX1 | GS homeobox 1 | gsh 1 | 1.0 | synaptosomes were pretreated with the following thioreductants: 5 mm glutathione gsh 1.25 mm n acetylcysteine nac and 1 mm dithiothreitol dtt ; and with the following antioxidants: 1 mm uric acid 1 mm melatonin 0.2 mm desferrioxamine and 1 mm bsa for 30 min before the addition of 1 mm |
| 11506 | SYP | synaptophysin | synaptophysin | 1.0 | dr. pierre potier in whose laboratories this work was performed for continuous support; dr. nicolas morel for help on immunological studies and the kind gift of antibodies against vamp/synaptobrevin synaptophysin and tubulin; dr. fran_amp_ccedil;ois marie meunier for sequence alignments; dr. seana o'regan for expertise in choline uptake mechanisms and critical reading; and dr. michael spedding and dr. esther |
| 399 | ALB | albumin | serum albumin | 1.0 | trite; ach acetylcholine; sin 1 3 morpholinosydnonimine; coa coenzyme a; chat choline acetyltransferase; vamp/synaptobrevin vesicular associated membrane protein; tca trichloroacetic acid; bsa bovine serum albumin; page polyacrylamide gel electrophoresis; ecl enhanced chemiluminescence; gsh glutathione; nac n acetylcysteine; dtt dithiothreitol. |
| 1912 | CHAT | choline acetyltransferase | choline acetyltransferase | 1.0 | onoo peroxynitrite; ach acetylcholine; sin 1 3 morpholinosydnonimine; coa coenzyme a; chat choline acetyltransferase; vamp/synaptobrevin vesicular associated membrane protein; tca trichloroacetic acid; bsa bovine serum albumin; page polyacrylamide gel electrophoresis; ecl enhanced chemiluminescence; gsh glutathione |
| 16014 | CASD1 | CAS1 domain containing 1 | o acetyltransferase | 1.0 | acetates|antioxidants|carbon radioisotopes|nitrates|oxidants|reducing agents|molsidomine|peroxynitric acid|3 morpholino sydnonimine|3 nitrotyrosine|acetylcholine|tyrosine|choline|uric acid|choline o acetyltransferase| |