Molecular biology changes associated with LRRK2 mutations in Parkinson's disease
Identifieur interne : 000D46 ( Main/Exploration ); précédent : 000D45; suivant : 000D47Molecular biology changes associated with LRRK2 mutations in Parkinson's disease
Auteurs : Yi Wei Lu [Singapour] ; Eng-King Tan [Singapour]Source :
- Journal of Neuroscience Research [ 0360-4012 ] ; 2008-07.
English descriptors
Abstract
Parkinson's disease (PD) is characterized by progressive dopaminergic neuronal loss in the substantia nigra. The recent discovery of leucine‐rich‐repeat kinase 2 gene (LRRK2) mutations in PD is significant because these mutations are the most common cause of autosomal dominant PD. Furthermore, a common recurrent mutation (G2019S) is associated with a significant proportion of nonfamilial PD, and a polymorphic variant (G2385R) has been found to increase the risk in the Asian race. The large LRRK2 protein of 280 kD contains three protein–protein interaction domains and two enzymatic domains, the Ras‐related GTPase and the kinase. Mutations in these domains have been described in PD patients. Preliminary evidence suggests that some types of LRRK2 mutations increase the kinase activity, and this is associated with significantly higher apoptotic cell death in dopaminergic cell lines and primary neurons; abolishing the kinase function ameliorates this cellular toxicity. It also appears that its GTPase domain can be activated independently, whereas the kinase activity strictly requires the GTPase activation. Mutations in the LRRK2 have displayed notable pleomorphic pathologies that might indicate an upstream role of LRRK2 in cellular signaling pathways. The identification of physiological substrates (likely to be involved in signaling and apotoptic pathways) of LRRK2 remains an important step in our understanding of the role of LRRK2 in the disease process. Further in vitro and in vivo studies will unravel the role of LRRK2 in cell signaling and its impact on proliferation, differentiation, and survival of neurons. © 2008 Wiley‐Liss, Inc.
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DOI: 10.1002/jnr.21656
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Neurosci. Res.</title><idno type="ISSN">0360-4012</idno><idno type="eISSN">1097-4547</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2008-07">2008-07</date><biblScope unit="volume">86</biblScope><biblScope unit="issue">9</biblScope><biblScope unit="page" from="1895">1895</biblScope><biblScope unit="page" to="1901">1901</biblScope></imprint><idno type="ISSN">0360-4012</idno></series><idno type="istex">BA8B824B9C7E95FF1F8B7E6E2A8ABBDE26D14EA6</idno><idno type="DOI">10.1002/jnr.21656</idno><idno type="ArticleID">JNR21656</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0360-4012</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Parkinson's disease</term><term>kinase activity</term><term>leucine‐rich repeat kinase 2</term><term>mutation</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Parkinson's disease (PD) is characterized by progressive dopaminergic neuronal loss in the substantia nigra. The recent discovery of leucine‐rich‐repeat kinase 2 gene (LRRK2) mutations in PD is significant because these mutations are the most common cause of autosomal dominant PD. Furthermore, a common recurrent mutation (G2019S) is associated with a significant proportion of nonfamilial PD, and a polymorphic variant (G2385R) has been found to increase the risk in the Asian race. The large LRRK2 protein of 280 kD contains three protein–protein interaction domains and two enzymatic domains, the Ras‐related GTPase and the kinase. Mutations in these domains have been described in PD patients. Preliminary evidence suggests that some types of LRRK2 mutations increase the kinase activity, and this is associated with significantly higher apoptotic cell death in dopaminergic cell lines and primary neurons; abolishing the kinase function ameliorates this cellular toxicity. It also appears that its GTPase domain can be activated independently, whereas the kinase activity strictly requires the GTPase activation. Mutations in the LRRK2 have displayed notable pleomorphic pathologies that might indicate an upstream role of LRRK2 in cellular signaling pathways. The identification of physiological substrates (likely to be involved in signaling and apotoptic pathways) of LRRK2 remains an important step in our understanding of the role of LRRK2 in the disease process. Further in vitro and in vivo studies will unravel the role of LRRK2 in cell signaling and its impact on proliferation, differentiation, and survival of neurons. © 2008 Wiley‐Liss, Inc.</div></front></TEI><affiliations><list><country><li>Singapour</li></country></list><tree><country name="Singapour"><noRegion><name sortKey="Lu, Yi Wei" sort="Lu, Yi Wei" uniqKey="Lu Y" first="Yi Wei" last="Lu">Yi Wei Lu</name></noRegion><name sortKey="Tan, Eng Ing" sort="Tan, Eng Ing" uniqKey="Tan E" first="Eng-King" last="Tan">Eng-King Tan</name><name sortKey="Tan, Eng Ing" sort="Tan, Eng Ing" uniqKey="Tan E" first="Eng-King" last="Tan">Eng-King Tan</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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