Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice.
Identifieur interne : 000413 ( PubMed/Checkpoint ); précédent : 000412; suivant : 000414Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice.
Auteurs : M. Yue [États-Unis] ; K M Hinkle [États-Unis] ; P. Davies [Royaume-Uni] ; E. Trushina [États-Unis] ; F C Fiesel [États-Unis] ; T A Christenson [États-Unis] ; A S Schroeder [États-Unis] ; L. Zhang [États-Unis] ; E. Bowles [États-Unis] ; B. Behrouz [États-Unis] ; S J Lincoln [États-Unis] ; J E Beevers [États-Unis] ; A J Milnerwood [Canada] ; A. Kurti [États-Unis] ; P J Mclean [États-Unis] ; J D Fryer [États-Unis] ; W. Springer [États-Unis] ; D W Dickson [États-Unis] ; M J Farrer [Canada] ; H L Melrose [États-Unis]Source :
- Neurobiology of disease [ 1095-953X ] ; 2015.
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 (KI) 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 24months of age. We find elevated kinase activity in the brain of both heterozygous and homozygous mice. Although normal at 6months, by 12months 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 KI mice, which are consistent with mitochondrial fission arrest. We anticipate that this G2019S mouse line 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.
DOI: 10.1016/j.nbd.2015.02.031
PubMed: 25836420
Affiliations:
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Yue</name><affiliation wicri:level="1"><nlm:affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.</nlm:affiliation><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="Hinkle, K M" sort="Hinkle, K M" uniqKey="Hinkle K" first="K M" last="Hinkle">K M Hinkle</name><affiliation wicri:level="1"><nlm:affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.</nlm:affiliation><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="Davies, P" sort="Davies, P" uniqKey="Davies P" first="P" last="Davies">P. 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Bowles</name><affiliation wicri:level="1"><nlm:affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.</nlm:affiliation><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="Behrouz, B" sort="Behrouz, B" uniqKey="Behrouz B" first="B" last="Behrouz">B. 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Kurti</name><affiliation wicri:level="1"><nlm:affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.</nlm:affiliation><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:affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; 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="Fryer, J D" sort="Fryer, J D" uniqKey="Fryer J" first="J D" last="Fryer">J D Fryer</name><affiliation wicri:level="1"><nlm:affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; 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. 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Electronic address: melrose.heather@mayo.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905</wicri:regionArea><wicri:noRegion>55905</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2015">2015</date><idno type="RBID">pubmed:25836420</idno><idno type="pmid">25836420</idno><idno type="doi">10.1016/j.nbd.2015.02.031</idno><idno type="wicri:Area/PubMed/Corpus">000491</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000491</idno><idno type="wicri:Area/PubMed/Curation">000491</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000491</idno><idno type="wicri:Area/PubMed/Checkpoint">000491</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000491</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice.</title><author><name sortKey="Yue, M" sort="Yue, M" uniqKey="Yue M" first="M" last="Yue">M. Yue</name><affiliation wicri:level="1"><nlm:affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.</nlm:affiliation><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="Hinkle, K M" sort="Hinkle, K M" uniqKey="Hinkle K" first="K M" last="Hinkle">K M Hinkle</name><affiliation wicri:level="1"><nlm:affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.</nlm:affiliation><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="Davies, P" sort="Davies, P" uniqKey="Davies P" first="P" last="Davies">P. Davies</name><affiliation wicri:level="1"><nlm:affiliation>MRC Phosphorylation Unit, University of Dundee, DD1 4HN, Scotland, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Phosphorylation Unit, University of Dundee, DD1 4HN, Scotland</wicri:regionArea><wicri:noRegion>Scotland</wicri:noRegion></affiliation></author><author><name sortKey="Trushina, E" sort="Trushina, E" uniqKey="Trushina E" first="E" last="Trushina">E. Trushina</name><affiliation wicri:level="2"><nlm:affiliation>Dept. of Neurology, Dept. of Pharmacology and Experimental Therapeutics, Mayo Clinic Rochester, Rochester, MN 55905, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Dept. of Neurology, Dept. of Pharmacology and Experimental Therapeutics, Mayo Clinic Rochester, Rochester, MN 55905</wicri:regionArea><placeName><region type="state">Minnesota</region></placeName></affiliation></author><author><name sortKey="Fiesel, F C" sort="Fiesel, F C" uniqKey="Fiesel F" first="F C" last="Fiesel">F C Fiesel</name><affiliation wicri:level="1"><nlm:affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.</nlm:affiliation><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="Christenson, T A" sort="Christenson, T A" uniqKey="Christenson T" first="T A" last="Christenson">T A Christenson</name><affiliation wicri:level="2"><nlm:affiliation>Mayo Clinic Electron Microscopy Core Facility, Rochester, MN 55905, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Mayo Clinic Electron Microscopy Core Facility, Rochester, MN 55905</wicri:regionArea><placeName><region type="state">Minnesota</region></placeName></affiliation></author><author><name sortKey="Schroeder, A S" sort="Schroeder, A S" uniqKey="Schroeder A" first="A S" last="Schroeder">A S Schroeder</name><affiliation wicri:level="2"><nlm:affiliation>Dept. of Neurology, Dept. of Pharmacology and Experimental Therapeutics, Mayo Clinic Rochester, Rochester, MN 55905, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Dept. of Neurology, Dept. of Pharmacology and Experimental Therapeutics, Mayo Clinic Rochester, Rochester, MN 55905</wicri:regionArea><placeName><region type="state">Minnesota</region></placeName></affiliation></author><author><name sortKey="Zhang, L" sort="Zhang, L" uniqKey="Zhang L" first="L" last="Zhang">L. Zhang</name><affiliation wicri:level="2"><nlm:affiliation>Dept. of Neurology, Dept. of Pharmacology and Experimental Therapeutics, Mayo Clinic Rochester, Rochester, MN 55905, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Dept. of Neurology, Dept. of Pharmacology and Experimental Therapeutics, Mayo Clinic Rochester, Rochester, MN 55905</wicri:regionArea><placeName><region type="state">Minnesota</region></placeName></affiliation></author><author><name sortKey="Bowles, E" sort="Bowles, E" uniqKey="Bowles E" first="E" last="Bowles">E. Bowles</name><affiliation wicri:level="1"><nlm:affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.</nlm:affiliation><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="Behrouz, B" sort="Behrouz, B" uniqKey="Behrouz B" first="B" last="Behrouz">B. Behrouz</name><affiliation wicri:level="1"><nlm:affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.</nlm:affiliation><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="Lincoln, S J" sort="Lincoln, S J" uniqKey="Lincoln S" first="S J" last="Lincoln">S J Lincoln</name><affiliation wicri:level="1"><nlm:affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.</nlm:affiliation><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="Beevers, J E" sort="Beevers, J E" uniqKey="Beevers J" first="J E" last="Beevers">J E Beevers</name><affiliation wicri:level="1"><nlm:affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.</nlm:affiliation><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="Milnerwood, A J" sort="Milnerwood, A J" uniqKey="Milnerwood A" first="A J" last="Milnerwood">A J Milnerwood</name><affiliation wicri:level="1"><nlm:affiliation>Center for Applied Neurogenetics, University of British Columbia, V6T 2B5, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Center for Applied Neurogenetics, 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:affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.</nlm:affiliation><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:affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; 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="Fryer, J D" sort="Fryer, J D" uniqKey="Fryer J" first="J D" last="Fryer">J D Fryer</name><affiliation wicri:level="1"><nlm:affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; 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:affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; 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 W" sort="Dickson, D W" uniqKey="Dickson D" first="D W" last="Dickson">D W Dickson</name><affiliation wicri:level="1"><nlm:affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; 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 J" sort="Farrer, M J" uniqKey="Farrer M" first="M J" last="Farrer">M J Farrer</name><affiliation wicri:level="1"><nlm:affiliation>Center for Applied Neurogenetics, University of British Columbia, V6T 2B5, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Center for Applied Neurogenetics, University of British Columbia, V6T 2B5</wicri:regionArea><wicri:noRegion>V6T 2B5</wicri:noRegion></affiliation></author><author><name sortKey="Melrose, H L" sort="Melrose, H L" uniqKey="Melrose H" first="H L" last="Melrose">H L Melrose</name><affiliation wicri:level="1"><nlm:affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA. Electronic address: melrose.heather@mayo.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; 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="eISSN">1095-953X</idno><imprint><date when="2015" type="published">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">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 (KI) 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 24months of age. We find elevated kinase activity in the brain of both heterozygous and homozygous mice. Although normal at 6months, by 12months 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 KI mice, which are consistent with mitochondrial fission arrest. We anticipate that this G2019S mouse line 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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">25836420</PMID><DateCreated><Year>2015</Year><Month>05</Month><Day>08</Day></DateCreated><DateCompleted><Year>2016</Year><Month>03</Month><Day>28</Day></DateCompleted><DateRevised><Year>2017</Year><Month>02</Month><Day>20</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1095-953X</ISSN><JournalIssue CitedMedium="Internet"><Volume>78</Volume><PubDate><Year>2015</Year><Month>Jun</Month></PubDate></JournalIssue><Title>Neurobiology of disease</Title><ISOAbbreviation>Neurobiol. Dis.</ISOAbbreviation></Journal><ArticleTitle>Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice.</ArticleTitle><Pagination><MedlinePgn>172-95</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.nbd.2015.02.031</ELocationID><ELocationID EIdType="pii" ValidYN="Y">S0969-9961(15)00099-6</ELocationID><Abstract><AbstractText>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 (KI) 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 24months of age. We find elevated kinase activity in the brain of both heterozygous and homozygous mice. Although normal at 6months, by 12months 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 KI mice, which are consistent with mitochondrial fission arrest. We anticipate that this G2019S mouse line 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.</AbstractText><CopyrightInformation>Copyright © 2015 Elsevier Inc. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Yue</LastName><ForeName>M</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hinkle</LastName><ForeName>K M</ForeName><Initials>KM</Initials><AffiliationInfo><Affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Davies</LastName><ForeName>P</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>MRC Phosphorylation Unit, University of Dundee, DD1 4HN, Scotland, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Trushina</LastName><ForeName>E</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Dept. of Neurology, Dept. of Pharmacology and Experimental Therapeutics, Mayo Clinic Rochester, Rochester, MN 55905, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fiesel</LastName><ForeName>F C</ForeName><Initials>FC</Initials><AffiliationInfo><Affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Christenson</LastName><ForeName>T A</ForeName><Initials>TA</Initials><AffiliationInfo><Affiliation>Mayo Clinic Electron Microscopy Core Facility, Rochester, MN 55905, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schroeder</LastName><ForeName>A S</ForeName><Initials>AS</Initials><AffiliationInfo><Affiliation>Dept. of Neurology, Dept. of Pharmacology and Experimental Therapeutics, Mayo Clinic Rochester, Rochester, MN 55905, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhang</LastName><ForeName>L</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Dept. of Neurology, Dept. of Pharmacology and Experimental Therapeutics, Mayo Clinic Rochester, Rochester, MN 55905, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bowles</LastName><ForeName>E</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Behrouz</LastName><ForeName>B</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lincoln</LastName><ForeName>S J</ForeName><Initials>SJ</Initials><AffiliationInfo><Affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Beevers</LastName><ForeName>J E</ForeName><Initials>JE</Initials><AffiliationInfo><Affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Milnerwood</LastName><ForeName>A J</ForeName><Initials>AJ</Initials><AffiliationInfo><Affiliation>Center for Applied Neurogenetics, University of British Columbia, V6T 2B5, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kurti</LastName><ForeName>A</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>McLean</LastName><ForeName>P J</ForeName><Initials>PJ</Initials><AffiliationInfo><Affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fryer</LastName><ForeName>J D</ForeName><Initials>JD</Initials><AffiliationInfo><Affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Springer</LastName><ForeName>W</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dickson</LastName><ForeName>D W</ForeName><Initials>DW</Initials><AffiliationInfo><Affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Farrer</LastName><ForeName>M J</ForeName><Initials>MJ</Initials><AffiliationInfo><Affiliation>Center for Applied Neurogenetics, University of British Columbia, V6T 2B5, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Melrose</LastName><ForeName>H L</ForeName><Initials>HL</Initials><AffiliationInfo><Affiliation>Dept. of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA. Electronic address: melrose.heather@mayo.edu.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>P50 NS040256</GrantID><Acronym>NS</Acronym><Agency>NINDS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 ES020715</GrantID><Acronym>ES</Acronym><Agency>NIEHS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>NS073740</GrantID><Acronym>NS</Acronym><Agency>NINDS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P01 NS040256</GrantID><Acronym>NS</Acronym><Agency>NINDS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>ES020715</GrantID><Acronym>ES</Acronym><Agency>NIEHS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>NS065860</GrantID><Acronym>NS</Acronym><Agency>NINDS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P50 NS072187</GrantID><Acronym>NS</Acronym><Agency>NINDS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>NS085070</GrantID><Acronym>NS</Acronym><Agency>NINDS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 NS073740</GrantID><Acronym>NS</Acronym><Agency>NINDS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 NS065860</GrantID><Acronym>NS</Acronym><Agency>NINDS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>NS072187</GrantID><Acronym>NS</Acronym><Agency>NINDS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>NS40256</GrantID><Acronym>NS</Acronym><Agency>NINDS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 NS085070</GrantID><Acronym>NS</Acronym><Agency>NINDS NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2015</Year><Month>03</Month><Day>31</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Neurobiol Dis</MedlineTA><NlmUniqueID>9500169</NlmUniqueID><ISSNLinking>0969-9961</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C558298">Mapt protein, mouse</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D016875">tau Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="D000071158">Leucine-Rich Repeat Serine-Threonine Protein Kinase-2</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="C495279">Lrrk2 protein, mouse</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 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Version="1">19667187</PMID></CommentsCorrections></CommentsCorrectionsList><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D001343" MajorTopicYN="N">Autophagy</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001921" MajorTopicYN="N">Brain</DescriptorName><QualifierName UI="Q000201" MajorTopicYN="Y">enzymology</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000648" MajorTopicYN="N">ultrastructure</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004298" MajorTopicYN="N">Dopamine</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D059290" MajorTopicYN="N">Dopaminergic Neurons</DescriptorName><QualifierName UI="Q000378" 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Yue</name></noRegion><name sortKey="Beevers, J E" sort="Beevers, J E" uniqKey="Beevers J" first="J E" last="Beevers">J E 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 A" sort="Christenson, T A" uniqKey="Christenson T" first="T A" last="Christenson">T A Christenson</name><name sortKey="Dickson, D W" sort="Dickson, D W" uniqKey="Dickson D" first="D W" last="Dickson">D W Dickson</name><name sortKey="Fiesel, F C" sort="Fiesel, F C" uniqKey="Fiesel F" first="F C" last="Fiesel">F C 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="Hinkle, K M" sort="Hinkle, K M" uniqKey="Hinkle K" first="K M" last="Hinkle">K M Hinkle</name><name sortKey="Kurti, A" sort="Kurti, A" uniqKey="Kurti A" first="A" last="Kurti">A. Kurti</name><name sortKey="Lincoln, S J" sort="Lincoln, S J" uniqKey="Lincoln S" first="S J" last="Lincoln">S J 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 L" sort="Melrose, H L" uniqKey="Melrose H" first="H L" last="Melrose">H L Melrose</name><name sortKey="Schroeder, A S" sort="Schroeder, A S" uniqKey="Schroeder A" first="A S" last="Schroeder">A S Schroeder</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 J" sort="Milnerwood, A J" uniqKey="Milnerwood A" first="A J" last="Milnerwood">A J Milnerwood</name></noRegion><name sortKey="Farrer, M J" sort="Farrer, M J" uniqKey="Farrer M" first="M J" last="Farrer">M J Farrer</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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