Lrrk2 phosphorylates alpha synuclein at serine 129: Parkinson disease implications.
Identifieur interne : 001E23 ( Main/Exploration ); précédent : 001E22; suivant : 001E24Lrrk2 phosphorylates alpha synuclein at serine 129: Parkinson disease implications.
Auteurs : Hong Qing [Canada] ; Winnie Wong ; Edith G. Mcgeer ; Patrick L. McgeerSource :
- Biochemical and biophysical research communications [ 1090-2104 ] ; 2009.
English descriptors
- KwdEn :
- Cell Line, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Mutation, Parkinson Disease (genetics), Parkinson Disease (metabolism), Phosphorylation, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases (metabolism), Serine (genetics), Serine (metabolism), alpha-Synuclein (genetics), alpha-Synuclein (metabolism).
- MESH :
- chemical , genetics : Serine, alpha-Synuclein.
- chemical , metabolism : Protein-Serine-Threonine Kinases, Serine, alpha-Synuclein.
- chemical : Leucine-Rich Repeat Serine-Threonine Protein Kinase-2.
- genetics : Parkinson Disease.
- metabolism : Parkinson Disease.
- Cell Line, Humans, Mutation, Phosphorylation, Protein Structure, Tertiary.
Abstract
Mutations in the alpha synuclein gene (SNCA) are the most potent cause of autosomal dominant Parkinson disease (PD) while mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause. We hypothesized that a direct interaction may exist between their protein products. Here we show that full-length Lrrk2 or fragments containing its kinase domain have a significant capacity to phosphorylate recombinant alpha synuclein (Asyn) at serine 129. Such phosphorylated Asyn is the major component of pathological deposits in PD. We further show that the G2019S mutation in Lrrk2, which is the most common genetic determinant of PD, has a significantly greater capacity than wild-type Lrrk2 to phosphorylate Asyn. This suggests that the G2019S mutant protein may cause PD by generating pathological levels of phosphorylated Asyn. Controlling Lrrk2 Asyn phosphokinase activity may be an approach to disease modifying therapy for PD and other synucleinopathies.
DOI: 10.1016/j.bbrc.2009.06.142
PubMed: 19576176
Affiliations:
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Mcgeer</name></author><author><name sortKey="Mcgeer, Patrick L" sort="Mcgeer, Patrick L" uniqKey="Mcgeer P" first="Patrick L" last="Mcgeer">Patrick L. Mcgeer</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2009">2009</date><idno type="RBID">pubmed:19576176</idno><idno type="pmid">19576176</idno><idno type="doi">10.1016/j.bbrc.2009.06.142</idno><idno type="wicri:Area/PubMed/Corpus">000E38</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000E38</idno><idno type="wicri:Area/PubMed/Curation">000E38</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000E38</idno><idno type="wicri:Area/PubMed/Checkpoint">000E38</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000E38</idno><idno type="wicri:Area/Ncbi/Merge">000B08</idno><idno type="wicri:Area/Ncbi/Curation">000B08</idno><idno type="wicri:Area/Ncbi/Checkpoint">000B08</idno><idno type="wicri:Area/Main/Merge">001F72</idno><idno type="wicri:Area/Main/Curation">001E23</idno><idno type="wicri:Area/Main/Exploration">001E23</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Lrrk2 phosphorylates alpha synuclein at serine 129: Parkinson disease implications.</title><author><name sortKey="Qing, Hong" sort="Qing, Hong" uniqKey="Qing H" first="Hong" last="Qing">Hong Qing</name><affiliation wicri:level="1"><nlm:affiliation>Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC</wicri:regionArea><wicri:noRegion>BC</wicri:noRegion></affiliation></author><author><name sortKey="Wong, Winnie" sort="Wong, Winnie" uniqKey="Wong W" first="Winnie" last="Wong">Winnie Wong</name></author><author><name sortKey="Mcgeer, Edith G" sort="Mcgeer, Edith G" uniqKey="Mcgeer E" first="Edith G" last="Mcgeer">Edith G. Mcgeer</name></author><author><name sortKey="Mcgeer, Patrick L" sort="Mcgeer, Patrick L" uniqKey="Mcgeer P" first="Patrick L" last="Mcgeer">Patrick L. Mcgeer</name></author></analytic><series><title level="j">Biochemical and biophysical research communications</title><idno type="eISSN">1090-2104</idno><imprint><date when="2009" type="published">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Cell Line</term><term>Humans</term><term>Leucine-Rich Repeat Serine-Threonine Protein Kinase-2</term><term>Mutation</term><term>Parkinson Disease (genetics)</term><term>Parkinson Disease (metabolism)</term><term>Phosphorylation</term><term>Protein Structure, Tertiary</term><term>Protein-Serine-Threonine Kinases (metabolism)</term><term>Serine (genetics)</term><term>Serine (metabolism)</term><term>alpha-Synuclein (genetics)</term><term>alpha-Synuclein (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Serine</term><term>alpha-Synuclein</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Protein-Serine-Threonine Kinases</term><term>Serine</term><term>alpha-Synuclein</term></keywords><keywords scheme="MESH" type="chemical" xml:lang="en"><term>Leucine-Rich Repeat Serine-Threonine Protein Kinase-2</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line</term><term>Humans</term><term>Mutation</term><term>Phosphorylation</term><term>Protein Structure, Tertiary</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Mutations in the alpha synuclein gene (SNCA) are the most potent cause of autosomal dominant Parkinson disease (PD) while mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause. We hypothesized that a direct interaction may exist between their protein products. Here we show that full-length Lrrk2 or fragments containing its kinase domain have a significant capacity to phosphorylate recombinant alpha synuclein (Asyn) at serine 129. Such phosphorylated Asyn is the major component of pathological deposits in PD. We further show that the G2019S mutation in Lrrk2, which is the most common genetic determinant of PD, has a significantly greater capacity than wild-type Lrrk2 to phosphorylate Asyn. This suggests that the G2019S mutant protein may cause PD by generating pathological levels of phosphorylated Asyn. Controlling Lrrk2 Asyn phosphokinase activity may be an approach to disease modifying therapy for PD and other synucleinopathies.</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><noCountry><name sortKey="Mcgeer, Edith G" sort="Mcgeer, Edith G" uniqKey="Mcgeer E" first="Edith G" last="Mcgeer">Edith G. Mcgeer</name><name sortKey="Mcgeer, Patrick L" sort="Mcgeer, Patrick L" uniqKey="Mcgeer P" first="Patrick L" last="Mcgeer">Patrick L. Mcgeer</name><name sortKey="Wong, Winnie" sort="Wong, Winnie" uniqKey="Wong W" first="Winnie" last="Wong">Winnie Wong</name></noCountry><country name="Canada"><noRegion><name sortKey="Qing, Hong" sort="Qing, Hong" uniqKey="Qing H" first="Hong" last="Qing">Hong Qing</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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