Biochemical and pathological characterization of Lrrk2
Identifieur interne : 001348 ( Main/Exploration ); précédent : 001347; suivant : 001349Biochemical and pathological characterization of Lrrk2
Auteurs : Benoit I. Giasson [États-Unis] ; Jason P. Covy [États-Unis] ; Nancy M. Bonini [États-Unis] ; Howard I. Hurtig [États-Unis] ; Matthew J. Farrer [États-Unis] ; John Q. Trojanowski [États-Unis] ; Vivianna M. Van Deerlin [États-Unis]Source :
- Annals of Neurology [ 0364-5134 ] ; 2006-02.
Abstract
Objective: Mutations in leucine‐rich repeat kinase 2 (LRRK2) recently have been identified as the most common genetic cause of late‐onset sporadic and familial Parkinson's disease (PD). The studies herein explore the biological and pathological properties of Lrrk2. Methods: Genetic analysis was performed to identify autopsied patients with the most common Lrrk2 mutation (G2019S). Using an antibody specific to Lrrk2, the biochemical and immunocytochemical distribution of Lrrk2 was assessed. Results: Three patients with the G2019S Lrrk2 mutation were identified. Two patients demonstrated classic PD with Lewy bodies, although concurrent pathological changes consistent with Alzheimer's disease were also present in one of these individuals. The third patient was characterized by parkinsonism without Lewy bodies but demonstrated dystrophic neurites in the substantia nigra intensely stained for Lrrk2. Lrrk2 accumulations were unique to this patient and Lrrk2 was not detected in other types of pathological inclusions. Biochemical analysis showed that Lrrk2 is predominantly a soluble approximately 250kDa cytoplasmic protein expressed throughout the brain but also in many other organs. Interpretation: The reasons for the selective predisposition of patients with mutations in LRRK2 to develop parkinsonism remains unclear, but Lrrk2 mutations may prime select neuronal populations to cellular insults that can lead to aberrant protein aggregation. Ann Neurol 2006;59:315–322
Url:
DOI: 10.1002/ana.20791
Affiliations:
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Farrer</name></author><author><name sortKey="Trojanowski, John Q" sort="Trojanowski, John Q" uniqKey="Trojanowski J" first="John Q." last="Trojanowski">John Q. Trojanowski</name></author><author><name sortKey="Van Deerlin, Vivianna M" sort="Van Deerlin, Vivianna M" uniqKey="Van Deerlin V" first="Vivianna M." last="Van Deerlin">Vivianna M. 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Giasson</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Pharmacology, Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Covy, Jason P" sort="Covy, Jason P" uniqKey="Covy J" first="Jason P." last="Covy">Jason P. Covy</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Pharmacology, Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Bonini, Nancy M" sort="Bonini, Nancy M" uniqKey="Bonini N" first="Nancy M." last="Bonini">Nancy M. Bonini</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Biology, Philadelphia</wicri:cityArea></affiliation><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Howard Hughes Medical Institute, Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Hurtig, Howard I" sort="Hurtig, Howard I" uniqKey="Hurtig H" first="Howard I." last="Hurtig">Howard I. Hurtig</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Neurology, Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Farrer, Matthew J" sort="Farrer, Matthew J" uniqKey="Farrer M" first="Matthew J." last="Farrer">Matthew J. Farrer</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Floride</region></placeName><wicri:cityArea>Department of Neuroscience, Mayo Clinic, Jacksonville</wicri:cityArea></affiliation></author><author><name sortKey="Trojanowski, John Q" sort="Trojanowski, John Q" uniqKey="Trojanowski J" first="John Q." last="Trojanowski">John Q. Trojanowski</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Pathology and Laboratory Medicine of the University of Pennsylvania, Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Van Deerlin, Vivianna M" sort="Van Deerlin, Vivianna M" uniqKey="Van Deerlin V" first="Vivianna M." last="Van Deerlin">Vivianna M. Van Deerlin</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Pathology and Laboratory Medicine of the University of Pennsylvania, Philadelphia</wicri:cityArea></affiliation></author></analytic><monogr></monogr><series><title level="j">Annals of Neurology</title><title level="j" type="sub">Official Journal of the American Neurological Association and the Child Neurology Society</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="2006-02">2006-02</date><biblScope unit="volume">59</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="315">315</biblScope><biblScope unit="page" to="322">322</biblScope></imprint><idno type="ISSN">0364-5134</idno></series><idno type="istex">F58D0606F4849FFB9BB4573BE664D9729F4D1A7F</idno><idno type="DOI">10.1002/ana.20791</idno><idno type="ArticleID">ANA20791</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: Mutations in leucine‐rich repeat kinase 2 (LRRK2) recently have been identified as the most common genetic cause of late‐onset sporadic and familial Parkinson's disease (PD). The studies herein explore the biological and pathological properties of Lrrk2. Methods: Genetic analysis was performed to identify autopsied patients with the most common Lrrk2 mutation (G2019S). Using an antibody specific to Lrrk2, the biochemical and immunocytochemical distribution of Lrrk2 was assessed. Results: Three patients with the G2019S Lrrk2 mutation were identified. Two patients demonstrated classic PD with Lewy bodies, although concurrent pathological changes consistent with Alzheimer's disease were also present in one of these individuals. The third patient was characterized by parkinsonism without Lewy bodies but demonstrated dystrophic neurites in the substantia nigra intensely stained for Lrrk2. Lrrk2 accumulations were unique to this patient and Lrrk2 was not detected in other types of pathological inclusions. Biochemical analysis showed that Lrrk2 is predominantly a soluble approximately 250kDa cytoplasmic protein expressed throughout the brain but also in many other organs. Interpretation: The reasons for the selective predisposition of patients with mutations in LRRK2 to develop parkinsonism remains unclear, but Lrrk2 mutations may prime select neuronal populations to cellular insults that can lead to aberrant protein aggregation. Ann Neurol 2006;59:315–322</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Floride</li><li>Pennsylvanie</li></region></list><tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Giasson, Benoit I" sort="Giasson, Benoit I" uniqKey="Giasson B" first="Benoit I." last="Giasson">Benoit I. Giasson</name></region><name sortKey="Bonini, Nancy M" sort="Bonini, Nancy M" uniqKey="Bonini N" first="Nancy M." last="Bonini">Nancy M. Bonini</name><name sortKey="Bonini, Nancy M" sort="Bonini, Nancy M" uniqKey="Bonini N" first="Nancy M." last="Bonini">Nancy M. Bonini</name><name sortKey="Covy, Jason P" sort="Covy, Jason P" uniqKey="Covy J" first="Jason P." last="Covy">Jason P. Covy</name><name sortKey="Farrer, Matthew J" sort="Farrer, Matthew J" uniqKey="Farrer M" first="Matthew J." last="Farrer">Matthew J. Farrer</name><name sortKey="Hurtig, Howard I" sort="Hurtig, Howard I" uniqKey="Hurtig H" first="Howard I." last="Hurtig">Howard I. Hurtig</name><name sortKey="Trojanowski, John Q" sort="Trojanowski, John Q" uniqKey="Trojanowski J" first="John Q." last="Trojanowski">John Q. Trojanowski</name><name sortKey="Van Deerlin, Vivianna M" sort="Van Deerlin, Vivianna M" uniqKey="Van Deerlin V" first="Vivianna M." last="Van Deerlin">Vivianna M. Van Deerlin</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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