Tau and α‐synuclein in susceptibility to, and dementia in, Parkinson's disease
Identifieur interne : 000F44 ( Main/Exploration ); précédent : 000F43; suivant : 000F45Tau and α‐synuclein in susceptibility to, and dementia in, Parkinson's disease
Auteurs : An Goris [Royaume-Uni, Belgique] ; Caroline H. Williams-Gray [Royaume-Uni] ; Graeme R. Clark [Royaume-Uni] ; Thomas Foltynie [Royaume-Uni] ; Simon J. G. Lewis [Royaume-Uni] ; Joanne Brown [Royaume-Uni] ; Maria Ban [Royaume-Uni] ; Maria G. Spillantini [Royaume-Uni] ; Alastair Compston [Royaume-Uni] ; David J. Burn [Royaume-Uni] ; Patrick F. Chinnery [Royaume-Uni] ; Roger A. Barker [Royaume-Uni] ; Stephen J. Sawcer [Royaume-Uni]Source :
- Annals of Neurology [ 0364-5134 ] ; 2007-08.
Abstract
Objective: Parkinson's disease (PD) is a neurodegenerative condition that typically presents as a movement disorder but is known to be associated with variable degrees of cognitive impairment including dementia. We investigated the genetic basis of susceptibility to and cognitive heterogeneity of this disease. Methods: In 659 PD patients, 109 of which were followed up for 3.5 years from diagnosis, and 2,176 control subjects, we studied candidate genes involved in protein aggregation and inclusion body formation, the pathological hallmark of parkinsonism: microtubule‐associated protein tau (MAPT), glycogen synthase kinase‐3β (GSK3B), and α‐synuclein (SNCA). Results: We observed that cognitive decline and the development of PD dementia are strongly associated (p = 10−4) with the inversion polymorphism containing MAPT. We also found a novel synergistic interaction between the MAPT inversion polymorphism and the single nucleotide polymorphism rs356219 from the 3′ region of SNCA. In our data, carrying a risk genotype at either of these loci marginally increases the risk for development of PD, whereas carrying the combination of risk genotypes at both loci approximately doubles the risk for development of the disease (p = 3 × 10−6). Interpretation: Our data support the hypothesis that tau and α‐synuclein are involved in shared or converging pathways in the pathogenesis of PD, and suggest that the tau inversion influences the development of cognitive impairment and dementia in patients with idiopathic PD. These findings have potentially important implications for understanding the interface between tau and α‐synuclein pathways in neurodegenerative disorders and for unraveling the biological basis for cognitive impairment and dementia in PD. Ann Neurol 2007
Url:
DOI: 10.1002/ana.21192
Affiliations:
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Lewis</name><affiliation wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Clinical Neurosciences (Cambridge Centre for Brain Repair), University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Brown, Joanne" sort="Brown, Joanne" uniqKey="Brown J" first="Joanne" last="Brown">Joanne Brown</name><affiliation wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Clinical Neurosciences (Cambridge Centre for Brain Repair), University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Ban, Maria" sort="Ban, Maria" uniqKey="Ban M" first="Maria" last="Ban">Maria Ban</name><affiliation wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Clinical Neurosciences (Neurology Unit), University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Spillantini, Maria G" sort="Spillantini, Maria G" uniqKey="Spillantini M" first="Maria G." last="Spillantini">Maria G. Spillantini</name><affiliation wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Clinical Neurosciences (Cambridge Centre for Brain Repair), University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Compston, Alastair" sort="Compston, Alastair" uniqKey="Compston A" first="Alastair" last="Compston">Alastair Compston</name><affiliation wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Clinical Neurosciences (Neurology Unit), University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Burn, David J" sort="Burn, David J" uniqKey="Burn D" first="David J." last="Burn">David J. Burn</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Neurology, School of Neurology, Neurobiology, and Psychiatry, University of Newcastle upon Tyne, Newcastle upon Tyne</wicri:regionArea><wicri:noRegion>Newcastle upon Tyne</wicri:noRegion></affiliation></author><author><name sortKey="Chinnery, Patrick F" sort="Chinnery, Patrick F" uniqKey="Chinnery P" first="Patrick F." last="Chinnery">Patrick F. Chinnery</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Neurology, School of Neurology, Neurobiology, and Psychiatry, University of Newcastle upon Tyne, Newcastle upon Tyne</wicri:regionArea><wicri:noRegion>Newcastle upon Tyne</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Human Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne</wicri:regionArea><wicri:noRegion>Newcastle upon Tyne</wicri:noRegion></affiliation></author><author><name sortKey="Barker, Roger A" sort="Barker, Roger A" uniqKey="Barker R" first="Roger A." last="Barker">Roger A. Barker</name><affiliation wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Clinical Neurosciences (Cambridge Centre for Brain Repair), University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Sawcer, Stephen J" sort="Sawcer, Stephen J" uniqKey="Sawcer S" first="Stephen J." last="Sawcer">Stephen J. Sawcer</name><affiliation wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Clinical Neurosciences (Neurology Unit), University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author></analytic><monogr></monogr><series><title level="j">Annals of Neurology</title><title level="j" type="abbrev">Ann Neurol.</title><idno type="ISSN">0364-5134</idno><idno type="eISSN">1531-8249</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2007-08">2007-08</date><biblScope unit="volume">62</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="145">145</biblScope><biblScope unit="page" to="153">153</biblScope></imprint><idno type="ISSN">0364-5134</idno></series><idno type="istex">22BF8F9DE662C209CD8B06BF8B522EBF245B53E4</idno><idno type="DOI">10.1002/ana.21192</idno><idno type="ArticleID">ANA21192</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0364-5134</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Objective: Parkinson's disease (PD) is a neurodegenerative condition that typically presents as a movement disorder but is known to be associated with variable degrees of cognitive impairment including dementia. We investigated the genetic basis of susceptibility to and cognitive heterogeneity of this disease. Methods: In 659 PD patients, 109 of which were followed up for 3.5 years from diagnosis, and 2,176 control subjects, we studied candidate genes involved in protein aggregation and inclusion body formation, the pathological hallmark of parkinsonism: microtubule‐associated protein tau (MAPT), glycogen synthase kinase‐3β (GSK3B), and α‐synuclein (SNCA). Results: We observed that cognitive decline and the development of PD dementia are strongly associated (p = 10−4) with the inversion polymorphism containing MAPT. We also found a novel synergistic interaction between the MAPT inversion polymorphism and the single nucleotide polymorphism rs356219 from the 3′ region of SNCA. In our data, carrying a risk genotype at either of these loci marginally increases the risk for development of PD, whereas carrying the combination of risk genotypes at both loci approximately doubles the risk for development of the disease (p = 3 × 10−6). Interpretation: Our data support the hypothesis that tau and α‐synuclein are involved in shared or converging pathways in the pathogenesis of PD, and suggest that the tau inversion influences the development of cognitive impairment and dementia in patients with idiopathic PD. These findings have potentially important implications for understanding the interface between tau and α‐synuclein pathways in neurodegenerative disorders and for unraveling the biological basis for cognitive impairment and dementia in PD. Ann Neurol 2007</div></front></TEI><affiliations><list><country><li>Belgique</li><li>Royaume-Uni</li></country><region><li>Angleterre</li><li>Angleterre de l'Est</li></region><settlement><li>Cambridge</li></settlement><orgName><li>Université de Cambridge</li></orgName></list><tree><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Goris, An" sort="Goris, An" uniqKey="Goris A" first="An" last="Goris">An Goris</name></region><name sortKey="Ban, Maria" sort="Ban, Maria" uniqKey="Ban M" first="Maria" last="Ban">Maria Ban</name><name sortKey="Barker, Roger A" sort="Barker, Roger A" uniqKey="Barker R" first="Roger A." last="Barker">Roger A. Barker</name><name sortKey="Brown, Joanne" sort="Brown, Joanne" uniqKey="Brown J" first="Joanne" last="Brown">Joanne Brown</name><name sortKey="Burn, David J" sort="Burn, David J" uniqKey="Burn D" first="David J." last="Burn">David J. Burn</name><name sortKey="Chinnery, Patrick F" sort="Chinnery, Patrick F" uniqKey="Chinnery P" first="Patrick F." last="Chinnery">Patrick F. Chinnery</name><name sortKey="Chinnery, Patrick F" sort="Chinnery, Patrick F" uniqKey="Chinnery P" first="Patrick F." last="Chinnery">Patrick F. Chinnery</name><name sortKey="Clark, Graeme R" sort="Clark, Graeme R" uniqKey="Clark G" first="Graeme R." last="Clark">Graeme R. Clark</name><name sortKey="Compston, Alastair" sort="Compston, Alastair" uniqKey="Compston A" first="Alastair" last="Compston">Alastair Compston</name><name sortKey="Foltynie, Thomas" sort="Foltynie, Thomas" uniqKey="Foltynie T" first="Thomas" last="Foltynie">Thomas Foltynie</name><name sortKey="Lewis, Simon J G" sort="Lewis, Simon J G" uniqKey="Lewis S" first="Simon J. G." last="Lewis">Simon J. G. Lewis</name><name sortKey="Sawcer, Stephen J" sort="Sawcer, Stephen J" uniqKey="Sawcer S" first="Stephen J." last="Sawcer">Stephen J. Sawcer</name><name sortKey="Spillantini, Maria G" sort="Spillantini, Maria G" uniqKey="Spillantini M" first="Maria G." last="Spillantini">Maria G. Spillantini</name><name sortKey="Williams Ray, Caroline H" sort="Williams Ray, Caroline H" uniqKey="Williams Ray C" first="Caroline H." last="Williams-Gray">Caroline H. Williams-Gray</name></country><country name="Belgique"><noRegion><name sortKey="Goris, An" sort="Goris, An" uniqKey="Goris A" first="An" last="Goris">An Goris</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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