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All 3 posts Subject: Pharmacology related to MAO knockout mice Please login to post Down

jsorex
(Hive Addict)
09-10-04 20:08
No 530689
      Pharmacology related to MAO knockout mice

http://www.sciencedaily.com/releases/2004/09/040910075119.htm

Source:   American Society For Biochemistry And Molecular Biology

Date:   2004-09-10

Spontaneous Mutation Produces New MAO A/B Knockout Mouse
Bethesda, MD - A combination of luck and scientific curiosity has produced a mouse lacking two isoenzymes, MAO A and MAO B, that have been linked to violent criminal behavior and Parkinson's disease. The MAO A/B knockout mouse should provide an excellent model in which to address the specific roles of these neurotransmitters and their receptors in anxiety and stress-related disorders.

The research appears as the "Paper of the Week" in the September 17 issue of the Journal of Biological Chemistry, an American Society for Biochemistry and Molecular Biology journal.

The monoamine oxidase isoenzymes MAO A and MAO B are involved in breaking down neurotransmitters. Higher or lower than normal amounts of these isoenzymes result in irregular neurotransmitter levels, causing abnormal behavior. Realizing the connection between neurotransmitter levels and behavior, psychiatrists routinely use MAO A inhibitors as antidepressants and MAO B inhibitors for Parkinson's disease.

By making knockout mice lacking either MAO A or MAO B, Jean C. Shih, a Professor at the University of Southern California School of Pharmacy, and her collaborators previously showed how each isoenzyme functions in the body. However, up until now, scientists have been unsuccessful at making a mouse lacking both MAO A and MAO B.

This all changed when Dr. Shih and her colleague, Professor Kevin Chen, noticed that one of the mice in an MAO B knockout litter was a little different from its littermates--it had a lower body weight and was extremely hyper-reactive when approached. Wanting to figure out why the mouse was different, the scientists decided to breed the mouse and examine its offspring.

The scientists discovered that the mice not only had high levels of neurotransmitters broken down by MAO B, as would be expected in mice lacking MAO B, but also had high levels of neurotransmitters broken down by MAO A. This indicated that somehow the MAO B knockout mouse had also lost its ability to produce MAO A.

"Both MAO A and MAO B are critically important," says Dr. Shih. "When both are missing in mice, brain neurotransmitters levels increase greatly and body weights are smaller. The mice also show anxiety and aggressive behavior, especially under stress."

Looking further into the matter, Dr. Shih determined that a spontaneous mutation in a single nucleic acid base pair in the MAO A gene created a premature stop which prevented it from being made into a protein. The scientists hypothesize that the mutation was due to elevated levels of the MAO B substrate phenylethylamine in the MAO B knockout mice. Phenylethylamine is a neuromodulator which, when broken down into its metabolites, has been shown to cause mutations in DNA.

"Interestingly," says Dr. Shih, "a similar single base pair mutation occurs in the MAO A gene in the men of a Dutch family who show impulsivity and aggressive behavior." This mutation in the Dutch family's MAO A also produces a premature stop codon which prevents production of the protein.

Dr. Shih's MAO A/B knockout mice should provide scientists with good model in which to study the combined actions of MAO A and MAO B, as well as examine the roles of neurotransmitters in anxiety- and stress-related disorders.

###

The Journal of Biological Chemistry's Papers of the Week is an online feature which highlights the top one percent of papers received by the journal. Brief summaries of the papers and explanations of why they were selected for this honor can be accessed directly from the home page of the Journal of Biological Chemistry online at www.jbc.org.

The American Society for Biochemistry and Molecular Biology (ASBMB) is a nonprofit scientific and educational organization with over 11,000 members in the United States and internationally. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, nonprofit research institutions, and industry.

Founded in 1906, the Society is based in Bethesda, Maryland, on the campus of the Federation of American Societies for Experimental Biology. The Society's primary purpose is to advance the sciences of biochemistry and molecular biology through its publications, the Journal of Biological Chemistry, The Journal of Lipid Research, Molecular and Cellular Proteomics, and Biochemistry and Molecular Biology Education, and the holding of scientific meetings.

For more information about ASBMB, see the Society's website at http://www.asbmb.org.

--------------------------------------------------------------------------------

This story has been adapted from a news release issued by American Society For Biochemistry And Molecular Biology.

methyl_ethyl
(Guardian)
09-11-04 01:45
No 530747
User Picture       Excellent Post Jrex

Good find Jrex,

Here is some related reading for those interested, Mods feel free to delete it if y'all think it is not hive worthy, I know some of us get excited about things many hive members think are trivial.

A Spontaneous Point Mutation Produces Monoamine Oxidase
A/B Knock-out Mice with Greatly Elevated Monoamines and
Anxiety-like Behavior
Kevin Chen, Daniel P. Holschneider, Weihua Wu, Igor Rebrin, and Jean C. Shih.
THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 279, No. 38, Issue of September 17, pp. 39645–39652, 2004

Abstract:

A spontaneous monoamine oxidase A (MAO A) mutation (A863T) in exon 8 introduced a premature stop codon, which produced MAO A/B double knock-out (KO) mice in a MAO B KO mouse colony. This mutation caused a nonsense-mediated mRNA decay and resulted in the absence of MAO A transcript, protein, and catalytic activity and abrogates a DraI restriction site. The MAO A/B KO mice showed reduced body weight compared with wild type mice. Brain levels of serotonin, norepinephrine, dopamine, and phenylethylamine increased,
and serotonin metabolite 5-hydroxyindoleacetic acid levels decreased, to a much greater degree than in either MAO A or B single KO mice. Observed chase/ escape and anxiety-like behavior in the MAO A/B KO mice, different from MAO A or B single KO mice, suggest that varying monoamine levels result in both a unique biochemical and behavioral phenotype. These mice will be useful models for studying the molecular basis
of disorders associated with abnormal monoamine
neurotransmitters.

regards,

methyl_ethyl

sorry about the formatting...

   Unipolar Mania, It's good for life... laugh

jsorex
(Hive Addict)
09-11-04 12:10
No 530839
      Methyl_Ethyl, did you notice this one issue of

Methyl_Ethyl, did you notice this one issue of one of my favourite jouranls was dedicated to the subject?

NeuroToxicology

Volume 25, Issues 1-2, Pages 1-338 (January 2004)
Monoamine Oxidases: Molecular, Pharmacological and Neurotoxicological Aspects A Tribute to Prof. Merton Sandler
Edited by A. Nicotra, S.H. Parvez, V. Glover, M. Sandler, S. Parvez and M. Minami

One good article in there is this one:

NeuroToxicology
Volume 25, Issues 1-2 , January 2004, Pages 11-20

DOI:10.1016/S0161-813X(03)00085-8

Progress in Monoamine Oxidase (MAO) Research in Relation to Genetic Engineering

Toshiharu Nagatsu,

Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan

Abstract
Monoamine oxidase (MAO) is an enzyme that oxidizes various physiologically and pathologically important monoamine neurotransmitters and hormones such as dopamine, noradrenaline, adrenaline, and serotonin. Two types of MAO, i.e. type A (MAO-A) and type B (MAO-B), were first discovered pharmacologically. MAO-A is inhibited by clorgyline; and MAO-B, by deprenyl. cDNAs MAO-A and MAO-B were cloned and their structures determined. MAO-A and MAO-B are made of similar but different polypeptides and encoded by different nuclear genes located on the X chromosome (Xp11.23). MAO-A and MAO-B genes consist of 15 exons with identical intron–exon organization, suggesting that they were derived from a common ancestral gene. Both enzymes require a flavin cofactor, flavin adenine dinucleotide (FAD), which binds to the cysteine residue of a pentapeptide sequence (Ser–Gly–Gly–Cys–Tyr). Both enzymes exist on the outer membrane of mitochondria of various types of cells in various tissues including the brain. In humans, MAO-A is abundant in the brain and liver, whereas the liver, lungs and intestine are rich in MAO-B. MAO-A oxidizes noradrenaline and serotonin; and MAO-B, mainly -phenylethylamine. In the human brain, MAO-A exists in catecholaminergic neurons, but MAO-B is found in serotonergic neurons and glial cells. MAO-A knockout mice exhibit increased serotonin levels and aggressive behavior, whereas MAO-B knockout mice show little behavioral change. The gene knockout mice of MAO-A or MAO-B, together with the observation that some humans lack MAO-A, MAO-B, or both have contributed to our understanding of the function of MAO-A and MAO-B in health and disease. MAO-A and MAO-B may be closely related to various neuropsychiatric disorders such as depression and Parkinson’s disease, and inhibitors of them are the subject of drug development for such diseases.

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	All 3 posts		Subject: Pharmacology related to MAO knockout mice		Please login to post		Down


		jsorex (Hive Addict) 09-10-04 20:08 No 530689				Pharmacology related to MAO knockout mice
						http://www.sciencedaily.com/releases/2004/09/040910075119.htm Source: American Society For Biochemistry And Molecular Biology Date: 2004-09-10 Spontaneous Mutation Produces New MAO A/B Knockout Mouse Bethesda, MD - A combination of luck and scientific curiosity has produced a mouse lacking two isoenzymes, MAO A and MAO B, that have been linked to violent criminal behavior and Parkinson's disease. The MAO A/B knockout mouse should provide an excellent model in which to address the specific roles of these neurotransmitters and their receptors in anxiety and stress-related disorders. The research appears as the "Paper of the Week" in the September 17 issue of the Journal of Biological Chemistry, an American Society for Biochemistry and Molecular Biology journal. The monoamine oxidase isoenzymes MAO A and MAO B are involved in breaking down neurotransmitters. Higher or lower than normal amounts of these isoenzymes result in irregular neurotransmitter levels, causing abnormal behavior. Realizing the connection between neurotransmitter levels and behavior, psychiatrists routinely use MAO A inhibitors as antidepressants and MAO B inhibitors for Parkinson's disease. By making knockout mice lacking either MAO A or MAO B, Jean C. Shih, a Professor at the University of Southern California School of Pharmacy, and her collaborators previously showed how each isoenzyme functions in the body. However, up until now, scientists have been unsuccessful at making a mouse lacking both MAO A and MAO B. This all changed when Dr. Shih and her colleague, Professor Kevin Chen, noticed that one of the mice in an MAO B knockout litter was a little different from its littermates--it had a lower body weight and was extremely hyper-reactive when approached. Wanting to figure out why the mouse was different, the scientists decided to breed the mouse and examine its offspring. The scientists discovered that the mice not only had high levels of neurotransmitters broken down by MAO B, as would be expected in mice lacking MAO B, but also had high levels of neurotransmitters broken down by MAO A. This indicated that somehow the MAO B knockout mouse had also lost its ability to produce MAO A. "Both MAO A and MAO B are critically important," says Dr. Shih. "When both are missing in mice, brain neurotransmitters levels increase greatly and body weights are smaller. The mice also show anxiety and aggressive behavior, especially under stress." Looking further into the matter, Dr. Shih determined that a spontaneous mutation in a single nucleic acid base pair in the MAO A gene created a premature stop which prevented it from being made into a protein. The scientists hypothesize that the mutation was due to elevated levels of the MAO B substrate phenylethylamine in the MAO B knockout mice. Phenylethylamine is a neuromodulator which, when broken down into its metabolites, has been shown to cause mutations in DNA. "Interestingly," says Dr. Shih, "a similar single base pair mutation occurs in the MAO A gene in the men of a Dutch family who show impulsivity and aggressive behavior." This mutation in the Dutch family's MAO A also produces a premature stop codon which prevents production of the protein. Dr. Shih's MAO A/B knockout mice should provide scientists with good model in which to study the combined actions of MAO A and MAO B, as well as examine the roles of neurotransmitters in anxiety- and stress-related disorders. ### The Journal of Biological Chemistry's Papers of the Week is an online feature which highlights the top one percent of papers received by the journal. Brief summaries of the papers and explanations of why they were selected for this honor can be accessed directly from the home page of the Journal of Biological Chemistry online at www.jbc.org. The American Society for Biochemistry and Molecular Biology (ASBMB) is a nonprofit scientific and educational organization with over 11,000 members in the United States and internationally. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, nonprofit research institutions, and industry. Founded in 1906, the Society is based in Bethesda, Maryland, on the campus of the Federation of American Societies for Experimental Biology. The Society's primary purpose is to advance the sciences of biochemistry and molecular biology through its publications, the Journal of Biological Chemistry, The Journal of Lipid Research, Molecular and Cellular Proteomics, and Biochemistry and Molecular Biology Education, and the holding of scientific meetings. For more information about ASBMB, see the Society's website at http://www.asbmb.org. -------------------------------------------------------------------------------- This story has been adapted from a news release issued by American Society For Biochemistry And Molecular Biology.



		methyl_ethyl (Guardian) 09-11-04 01:45 No 530747				Excellent Post Jrex
						Good find Jrex, Here is some related reading for those interested, Mods feel free to delete it if y'all think it is not hive worthy, I know some of us get excited about things many hive members think are trivial. A Spontaneous Point Mutation Produces Monoamine Oxidase A/B Knock-out Mice with Greatly Elevated Monoamines and Anxiety-like Behavior Kevin Chen, Daniel P. Holschneider, Weihua Wu, Igor Rebrin, and Jean C. Shih. THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 279, No. 38, Issue of September 17, pp. 39645–39652, 2004 Abstract: A spontaneous monoamine oxidase A (MAO A) mutation (A863T) in exon 8 introduced a premature stop codon, which produced MAO A/B double knock-out (KO) mice in a MAO B KO mouse colony. This mutation caused a nonsense-mediated mRNA decay and resulted in the absence of MAO A transcript, protein, and catalytic activity and abrogates a DraI restriction site. The MAO A/B KO mice showed reduced body weight compared with wild type mice. Brain levels of serotonin, norepinephrine, dopamine, and phenylethylamine increased, and serotonin metabolite 5-hydroxyindoleacetic acid levels decreased, to a much greater degree than in either MAO A or B single KO mice. Observed chase/ escape and anxiety-like behavior in the MAO A/B KO mice, different from MAO A or B single KO mice, suggest that varying monoamine levels result in both a unique biochemical and behavioral phenotype. These mice will be useful models for studying the molecular basis of disorders associated with abnormal monoamine neurotransmitters. regards, methyl_ethyl sorry about the formatting... Unipolar Mania, It's good for life...



		jsorex (Hive Addict) 09-11-04 12:10 No 530839				Methyl_Ethyl, did you notice this one issue of
						Methyl_Ethyl, did you notice this one issue of one of my favourite jouranls was dedicated to the subject? NeuroToxicology Volume 25, Issues 1-2, Pages 1-338 (January 2004) Monoamine Oxidases: Molecular, Pharmacological and Neurotoxicological Aspects A Tribute to Prof. Merton Sandler Edited by A. Nicotra, S.H. Parvez, V. Glover, M. Sandler, S. Parvez and M. Minami One good article in there is this one: NeuroToxicology Volume 25, Issues 1-2 , January 2004, Pages 11-20 DOI:10.1016/S0161-813X(03)00085-8 Progress in Monoamine Oxidase (MAO) Research in Relation to Genetic Engineering Toshiharu Nagatsu, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan Abstract Monoamine oxidase (MAO) is an enzyme that oxidizes various physiologically and pathologically important monoamine neurotransmitters and hormones such as dopamine, noradrenaline, adrenaline, and serotonin. Two types of MAO, i.e. type A (MAO-A) and type B (MAO-B), were first discovered pharmacologically. MAO-A is inhibited by clorgyline; and MAO-B, by deprenyl. cDNAs MAO-A and MAO-B were cloned and their structures determined. MAO-A and MAO-B are made of similar but different polypeptides and encoded by different nuclear genes located on the X chromosome (Xp11.23). MAO-A and MAO-B genes consist of 15 exons with identical intron–exon organization, suggesting that they were derived from a common ancestral gene. Both enzymes require a flavin cofactor, flavin adenine dinucleotide (FAD), which binds to the cysteine residue of a pentapeptide sequence (Ser–Gly–Gly–Cys–Tyr). Both enzymes exist on the outer membrane of mitochondria of various types of cells in various tissues including the brain. In humans, MAO-A is abundant in the brain and liver, whereas the liver, lungs and intestine are rich in MAO-B. MAO-A oxidizes noradrenaline and serotonin; and MAO-B, mainly -phenylethylamine. In the human brain, MAO-A exists in catecholaminergic neurons, but MAO-B is found in serotonergic neurons and glial cells. MAO-A knockout mice exhibit increased serotonin levels and aggressive behavior, whereas MAO-B knockout mice show little behavioral change. The gene knockout mice of MAO-A or MAO-B, together with the observation that some humans lack MAO-A, MAO-B, or both have contributed to our understanding of the function of MAO-A and MAO-B in health and disease. MAO-A and MAO-B may be closely related to various neuropsychiatric disorders such as depression and Parkinson’s disease, and inhibitors of them are the subject of drug development for such diseases.

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