ParkinsonCanadaV1, Main, Exploration, bibRecord, 000573

Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock in mice

Identifieur interne : 000573 ( Main/Exploration ); précédent : 000572; suivant : 000574

Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock in mice

Auteurs : M. Yue [États-Unis] ; K. Hinkle [États-Unis] ; P. Davies [Royaume-Uni] ; E. Trushina [États-Unis] ; F. Fiesel [États-Unis] ; T. Christenson [États-Unis] ; A. Schroeder [États-Unis] ; L. Zhang [États-Unis] ; E. Bowles [États-Unis] ; B. Behrouz [États-Unis] ; S. Lincoln [États-Unis] ; J. Beevers [États-Unis] ; A. Milnerwood [Canada] ; A. Kurti [États-Unis] ; P. J. Mclean [États-Unis] ; J. D. Fryer [États-Unis] ; W. Springer [États-Unis] ; D. Dickson [États-Unis] ; M. Farrer [Canada] ; H. Melrose [États-Unis]

Source :

Neurobiology of disease [ 0969-9961 ] ; 2015.

RBID : PMC:4526103

English descriptors

KwdEn :
- Animals, Autophagy (genetics), Brain (enzymology), Brain (metabolism), Brain (ultrastructure), Dopamine (metabolism), Dopaminergic Neurons (metabolism), Female, Gene Knock-In Techniques, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria (metabolism), Mitochondria (ultrastructure), Motor Activity (genetics), Protein-Serine-Threonine Kinases (genetics), Protein-Serine-Threonine Kinases (physiology), Rotarod Performance Test, tau Proteins (metabolism).
MESH :
- chemical , genetics : Protein-Serine-Threonine Kinases.
- chemical , metabolism : Dopamine, tau Proteins.
- enzymology : Brain.
- genetics : Autophagy, Motor Activity.
- metabolism : Brain, Dopaminergic Neurons, Mitochondria.
- chemical , physiology : Protein-Serine-Threonine Kinases.
- ultrastructure : Brain, Mitochondria.
- Animals, Female, Gene Knock-In Techniques, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Rotarod Performance Test.

Abstract

Mutations in the LRRK2 gene represent the most common genetic cause of late onset Parkinson’s disease. The physiological and pathological roles of LRRK2 are yet to be fully determined but evidence points towards LRRK2 mutations causing a gain in kinase function, impacting on neuronal maintenance, vesicular dynamics and neurotransmitter release. To explore the role of physiological levels of mutant LRRK2, we created knock in mice harboring the most common LRRK2 mutation G2019S in their own genome. We have performed comprehensive dopaminergic, behavioral and neuropathological analyses in this model up to 24 months of age. We find elevated kinase activity in the brain of both heterozygous and homozygous mice. Although normal at 6 months, by 12 months of age, basal and pharmacologically induced extracellular release of dopamine is impaired in both heterozygous and homozygous mice, corroborating previous findings in transgenic models over-expressing mutant LRRK2. Via in vivo microdialysis measurement of basal and drug- evoked extracellular release of dopamine and its metabolites, our findings indicate that exocytotic release from the vesicular pool is impaired. Furthermore, profound mitochondrial abnormalities are evident in the striatum of older homozygous G2019S mice, which are consistent with mitochondrial fission arrest. We anticipate the G2019S will be a useful pre-clinical model for further evaluation of early mechanistic events in LRRK2 pathogenesis and for second-hit approaches to model disease progression.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526103

DOI: 10.1016/j.nbd.2015.02.031
PubMed: 25836420
PubMed Central: 4526103

Affiliations:

Canada, Royaume-Uni, États-Unis

Le document en format XML

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<country xml:lang="fr">Canada</country>
<wicri:regionArea>Center for Applied Genetics, University of British Columbia, V6T 2B5</wicri:regionArea>
<wicri:noRegion>V6T 2B5</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Kurti, A" sort="Kurti, A" uniqKey="Kurti A" first="A." last="Kurti">A. Kurti</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Dept of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Dept of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224</wicri:regionArea>
<wicri:noRegion>Jacksonville FL 32224</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Mclean, P J" sort="Mclean, P J" uniqKey="Mclean P" first="P. J." last="Mclean">P. J. Mclean</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Dept of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Dept of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224</wicri:regionArea>
<wicri:noRegion>Jacksonville FL 32224</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Fryer, J D" sort="Fryer, J D" uniqKey="Fryer J" first="J. D." last="Fryer">J. D. Fryer</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Dept of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Dept of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224</wicri:regionArea>
<wicri:noRegion>Jacksonville FL 32224</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905</wicri:regionArea>
<wicri:noRegion>55905</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Springer, W" sort="Springer, W" uniqKey="Springer W" first="W." last="Springer">W. Springer</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Dept of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Dept of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224</wicri:regionArea>
<wicri:noRegion>Jacksonville FL 32224</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905</wicri:regionArea>
<wicri:noRegion>55905</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Dickson, D" sort="Dickson, D" uniqKey="Dickson D" first="D." last="Dickson">D. Dickson</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Dept of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Dept of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224</wicri:regionArea>
<wicri:noRegion>Jacksonville FL 32224</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905</wicri:regionArea>
<wicri:noRegion>55905</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Farrer, M" sort="Farrer, M" uniqKey="Farrer M" first="M." last="Farrer">M. Farrer</name>
<affiliation wicri:level="1"><nlm:aff id="A5">Center for Applied Genetics, University of British Columbia, V6T 2B5, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Center for Applied Genetics, University of British Columbia, V6T 2B5</wicri:regionArea>
<wicri:noRegion>V6T 2B5</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Melrose, H" sort="Melrose, H" uniqKey="Melrose H" first="H." last="Melrose">H. Melrose</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Dept of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Dept of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224</wicri:regionArea>
<wicri:noRegion>Jacksonville FL 32224</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905</wicri:regionArea>
<wicri:noRegion>55905</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j">Neurobiology of disease</title>
<idno type="ISSN">0969-9961</idno>
<idno type="eISSN">1095-953X</idno>
<imprint><date when="2015">2015</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Autophagy (genetics)</term>
<term>Brain (enzymology)</term>
<term>Brain (metabolism)</term>
<term>Brain (ultrastructure)</term>
<term>Dopamine (metabolism)</term>
<term>Dopaminergic Neurons (metabolism)</term>
<term>Female</term>
<term>Gene Knock-In Techniques</term>
<term>Leucine-Rich Repeat Serine-Threonine Protein Kinase-2</term>
<term>Male</term>
<term>Mice</term>
<term>Mice, Inbred C57BL</term>
<term>Mice, Transgenic</term>
<term>Mitochondria (metabolism)</term>
<term>Mitochondria (ultrastructure)</term>
<term>Motor Activity (genetics)</term>
<term>Protein-Serine-Threonine Kinases (genetics)</term>
<term>Protein-Serine-Threonine Kinases (physiology)</term>
<term>Rotarod Performance Test</term>
<term>tau Proteins (metabolism)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Protein-Serine-Threonine Kinases</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Dopamine</term>
<term>tau Proteins</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Brain</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Autophagy</term>
<term>Motor Activity</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Brain</term>
<term>Dopaminergic Neurons</term>
<term>Mitochondria</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Protein-Serine-Threonine Kinases</term>
</keywords>
<keywords scheme="MESH" qualifier="ultrastructure" xml:lang="en"><term>Brain</term>
<term>Mitochondria</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Female</term>
<term>Gene Knock-In Techniques</term>
<term>Leucine-Rich Repeat Serine-Threonine Protein Kinase-2</term>
<term>Male</term>
<term>Mice</term>
<term>Mice, Inbred C57BL</term>
<term>Mice, Transgenic</term>
<term>Rotarod Performance Test</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p id="P2">Mutations in the <italic>LRRK2</italic>
 gene represent the most common genetic cause of late onset Parkinson’s disease. The physiological and pathological roles of LRRK2 are yet to be fully determined but evidence points towards <italic>LRRK2</italic>
 mutations causing a gain in kinase function, impacting on neuronal maintenance, vesicular dynamics and neurotransmitter release. To explore the role of physiological levels of mutant LRRK2, we created knock in mice harboring the most common LRRK2 mutation G2019S in their own genome. We have performed comprehensive dopaminergic, behavioral and neuropathological analyses in this model up to 24 months of age. We find elevated kinase activity in the brain of both heterozygous and homozygous mice. Although normal at 6 months, by 12 months of age, basal and pharmacologically induced extracellular release of dopamine is impaired in both heterozygous and homozygous mice, corroborating previous findings in transgenic models over-expressing mutant LRRK2. Via <italic>in vivo</italic>
 microdialysis measurement of basal and drug- evoked extracellular release of dopamine and its metabolites, our findings indicate that exocytotic release from the vesicular pool is impaired. Furthermore, profound mitochondrial abnormalities are evident in the striatum of older homozygous G2019S mice, which are consistent with mitochondrial fission arrest. We anticipate the G2019S will be a useful pre-clinical model for further evaluation of early mechanistic events in LRRK2 pathogenesis and for second-hit approaches to model disease progression.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>Canada</li>
<li>Royaume-Uni</li>
<li>États-Unis</li>
</country>
</list>
<tree><country name="États-Unis"><noRegion><name sortKey="Yue, M" sort="Yue, M" uniqKey="Yue M" first="M." last="Yue">M. Yue</name>
</noRegion>
<name sortKey="Beevers, J" sort="Beevers, J" uniqKey="Beevers J" first="J." last="Beevers">J. Beevers</name>
<name sortKey="Behrouz, B" sort="Behrouz, B" uniqKey="Behrouz B" first="B." last="Behrouz">B. Behrouz</name>
<name sortKey="Bowles, E" sort="Bowles, E" uniqKey="Bowles E" first="E." last="Bowles">E. Bowles</name>
<name sortKey="Christenson, T" sort="Christenson, T" uniqKey="Christenson T" first="T." last="Christenson">T. Christenson</name>
<name sortKey="Dickson, D" sort="Dickson, D" uniqKey="Dickson D" first="D." last="Dickson">D. Dickson</name>
<name sortKey="Dickson, D" sort="Dickson, D" uniqKey="Dickson D" first="D." last="Dickson">D. Dickson</name>
<name sortKey="Fiesel, F" sort="Fiesel, F" uniqKey="Fiesel F" first="F." last="Fiesel">F. Fiesel</name>
<name sortKey="Fryer, J D" sort="Fryer, J D" uniqKey="Fryer J" first="J. D." last="Fryer">J. D. Fryer</name>
<name sortKey="Fryer, J D" sort="Fryer, J D" uniqKey="Fryer J" first="J. D." last="Fryer">J. D. Fryer</name>
<name sortKey="Hinkle, K" sort="Hinkle, K" uniqKey="Hinkle K" first="K." last="Hinkle">K. Hinkle</name>
<name sortKey="Kurti, A" sort="Kurti, A" uniqKey="Kurti A" first="A." last="Kurti">A. Kurti</name>
<name sortKey="Lincoln, S" sort="Lincoln, S" uniqKey="Lincoln S" first="S." last="Lincoln">S. Lincoln</name>
<name sortKey="Mclean, P J" sort="Mclean, P J" uniqKey="Mclean P" first="P. J." last="Mclean">P. J. Mclean</name>
<name sortKey="Melrose, H" sort="Melrose, H" uniqKey="Melrose H" first="H." last="Melrose">H. Melrose</name>
<name sortKey="Melrose, H" sort="Melrose, H" uniqKey="Melrose H" first="H." last="Melrose">H. Melrose</name>
<name sortKey="Schroeder, A" sort="Schroeder, A" uniqKey="Schroeder A" first="A." last="Schroeder">A. Schroeder</name>
<name sortKey="Springer, W" sort="Springer, W" uniqKey="Springer W" first="W." last="Springer">W. Springer</name>
<name sortKey="Springer, W" sort="Springer, W" uniqKey="Springer W" first="W." last="Springer">W. Springer</name>
<name sortKey="Trushina, E" sort="Trushina, E" uniqKey="Trushina E" first="E." last="Trushina">E. Trushina</name>
<name sortKey="Zhang, L" sort="Zhang, L" uniqKey="Zhang L" first="L." last="Zhang">L. Zhang</name>
</country>
<country name="Royaume-Uni"><noRegion><name sortKey="Davies, P" sort="Davies, P" uniqKey="Davies P" first="P." last="Davies">P. Davies</name>
</noRegion>
</country>
<country name="Canada"><noRegion><name sortKey="Milnerwood, A" sort="Milnerwood, A" uniqKey="Milnerwood A" first="A." last="Milnerwood">A. Milnerwood</name>
</noRegion>
<name sortKey="Farrer, M" sort="Farrer, M" uniqKey="Farrer M" first="M." last="Farrer">M. Farrer</name>
</country>
</tree>
</affiliations>
</record>

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La maladie de Parkinson au Canada (serveur d'exploration)

Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock in mice

Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock in mice

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	La maladie de Parkinson au Canada (serveur d'exploration)
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