Parkinson's disease: the first common neurological disease due to auto-intoxication?
Identifieur interne : 001448 ( Main/Exploration ); précédent : 001447; suivant : 001449Parkinson's disease: the first common neurological disease due to auto-intoxication?
Auteurs : A. C. Williams ; L. S. Cartwright [Royaume-Uni] ; D. B. Ramsden [Royaume-Uni]Source :
- QJM [ 1460-2725 ] ; 2005-03.
Abstract
Parkinson's disease may be a disease of autointoxication. N-methylated pyridines (e.g. MPP+) are well-established dopaminergic toxins, and the xenobiotic enzyme nicotinamide N-methyltransferase (NNMT) can convert pyridines such as 4-phenylpyridine into MPP+, using S-adenosyl methionine (SAM) as the methyl donor. NNMT has recently been shown to be present in the human brain, a necessity for neurotoxicity, because charged compounds cannot cross the blood-brain barrier. Moreover, it is present in increased concentration in parkinsonian brain. This increase may be part genetic predisposition, and part induction, by excessive exposure to its substrates (particularly nicotinamide) or stress. Elevated enzymic activity would increase MPP+-like compounds such as N-methyl nicotinamide at the same time as decreasing intraneuronal nicotinamide, a neuroprotectant at several levels, creating multiple hits, because Complex 1 would be poisoned and be starved of its major substrate NADH. Developing xenobiotic enzyme inhibitors of NNMT for individuals, or dietary modification for the whole population, could be an important change in thinking on primary and secondary prevention.
Url:
DOI: 10.1093/qjmed/hci027
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Williams</name><affiliation><wicri:noCountry code="no comma">Neurosciences and</wicri:noCountry></affiliation><affiliation><wicri:noCountry code="no comma">From the Divisions of</wicri:noCountry></affiliation></author><author><name sortKey="Cartwright, L S" sort="Cartwright, L S" uniqKey="Cartwright L" first="L. S." last="Cartwright">L. S. Cartwright</name><affiliation wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Medical Sciences, University of Birmingham, Birmingham</wicri:regionArea><placeName><settlement type="city">Birmingham</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Midlands de l'Ouest</region></placeName><orgName type="university">Université de Birmingham</orgName></affiliation><affiliation><wicri:noCountry code="no comma">From the Divisions of</wicri:noCountry></affiliation></author><author><name sortKey="Ramsden, D B" sort="Ramsden, D B" uniqKey="Ramsden D" first="D. B." last="Ramsden">D. B. Ramsden</name><affiliation wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Medical Sciences, University of Birmingham, Birmingham</wicri:regionArea><placeName><settlement type="city">Birmingham</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Midlands de l'Ouest</region></placeName><orgName type="university">Université de Birmingham</orgName></affiliation><affiliation><wicri:noCountry code="no comma">From the Divisions of</wicri:noCountry></affiliation></author></analytic><monogr></monogr><series><title level="j">QJM</title><title level="j" type="abbrev">QJM</title><idno type="ISSN">1460-2725</idno><idno type="eISSN">1460-2393</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2005-03">2005-03</date><biblScope unit="volume">98</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="215">215</biblScope><biblScope unit="page" to="226">226</biblScope></imprint><idno type="ISSN">1460-2725</idno></series><idno type="istex">76486CDEE8C55666FCB08616D0A17AFC5AEC7D0F</idno><idno type="DOI">10.1093/qjmed/hci027</idno><idno type="local">hci027</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1460-2725</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Parkinson's disease may be a disease of autointoxication. N-methylated pyridines (e.g. MPP+) are well-established dopaminergic toxins, and the xenobiotic enzyme nicotinamide N-methyltransferase (NNMT) can convert pyridines such as 4-phenylpyridine into MPP+, using S-adenosyl methionine (SAM) as the methyl donor. NNMT has recently been shown to be present in the human brain, a necessity for neurotoxicity, because charged compounds cannot cross the blood-brain barrier. Moreover, it is present in increased concentration in parkinsonian brain. This increase may be part genetic predisposition, and part induction, by excessive exposure to its substrates (particularly nicotinamide) or stress. Elevated enzymic activity would increase MPP+-like compounds such as N-methyl nicotinamide at the same time as decreasing intraneuronal nicotinamide, a neuroprotectant at several levels, creating multiple hits, because Complex 1 would be poisoned and be starved of its major substrate NADH. Developing xenobiotic enzyme inhibitors of NNMT for individuals, or dietary modification for the whole population, could be an important change in thinking on primary and secondary prevention.</div></front></TEI><affiliations><list><country><li>Royaume-Uni</li></country><region><li>Angleterre</li><li>Midlands de l'Ouest</li></region><settlement><li>Birmingham</li></settlement><orgName><li>Université de Birmingham</li></orgName></list><tree><noCountry><name sortKey="Williams, A C" sort="Williams, A C" uniqKey="Williams A" first="A. C." last="Williams">A. C. Williams</name></noCountry><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Cartwright, L S" sort="Cartwright, L S" uniqKey="Cartwright L" first="L. S." last="Cartwright">L. S. Cartwright</name></region><name sortKey="Ramsden, D B" sort="Ramsden, D B" uniqKey="Ramsden D" first="D. B." last="Ramsden">D. B. Ramsden</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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