Chronic and acute LRRK2 silencing has no long-term behavioral effects, whereas wild-type and mutant LRRK2 overexpression induce motor and cognitive deficits and altered regulation of dopamine release.
Identifieur interne : 000411 ( PubMed/Curation ); précédent : 000410; suivant : 000412Chronic and acute LRRK2 silencing has no long-term behavioral effects, whereas wild-type and mutant LRRK2 overexpression induce motor and cognitive deficits and altered regulation of dopamine release.
Auteurs : Mattia Volta [Canada] ; Stefano Cataldi [Canada] ; Dayne Beccano-Kelly [Canada] ; Lise Munsie [Canada] ; Igor Tatarnikov [Canada] ; Patrick Chou [Canada] ; Sabrina Bergeron [Canada] ; Emma Mitchell [Canada] ; Roscoe Lim [Canada] ; Jaskaran Khinda [Canada] ; Alejandro Lloret [États-Unis] ; C Frank Bennett [États-Unis] ; Carmela Paradiso [Italie] ; Michele Morari [Italie] ; Matthew J. Farrer [Canada] ; Austen J. Milnerwood [Canada]Source :
- Parkinsonism & related disorders [ 1873-5126 ] ; 2015.
English descriptors
- KwdEn :
- Animals, Blotting, Western, Chromosomes, Artificial, Bacterial, Cognition Disorders (genetics), Corpus Striatum (metabolism), Disease Models, Animal, Dopamine (secretion), Humans, Immunohistochemistry, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity (physiology), Parkinson Disease (genetics), Parkinson Disease (metabolism), Protein-Serine-Threonine Kinases (genetics).
- MESH :
- chemical , genetics : Protein-Serine-Threonine Kinases.
- chemical , secretion : Dopamine.
- genetics : Cognition Disorders, Parkinson Disease.
- metabolism : Corpus Striatum, Parkinson Disease.
- physiology : Motor Activity.
- Animals, Blotting, Western, Chromosomes, Artificial, Bacterial, Disease Models, Animal, Humans, Immunohistochemistry, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic.
Abstract
Germline silencing of the PD-related protein LRRK2 does not alter glutamate or dopamine release in adult mice, but some exploratory abnormalities have been reported with ageing. Contrastingly, high levels of human LRRK2 cause locomotor alterations and cognitive deficits accompanied by reduced striatal dopamine levels, with the latter also observed in G2019S mutant mice. Comparative cognitive and motor behavioral testing of LRRK2 KO, overexpressor and mutant overexpressor mice has not previously been reported.
DOI: 10.1016/j.parkreldis.2015.07.025
PubMed: 26282470
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pubmed:26282470Le document en format XML
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<term>Corpus Striatum (metabolism)</term>
<term>Disease Models, Animal</term>
<term>Dopamine (secretion)</term>
<term>Humans</term>
<term>Immunohistochemistry</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>Motor Activity (physiology)</term>
<term>Parkinson Disease (genetics)</term>
<term>Parkinson Disease (metabolism)</term>
<term>Protein-Serine-Threonine Kinases (genetics)</term>
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<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Protein-Serine-Threonine Kinases</term>
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<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Cognition Disorders</term>
<term>Parkinson Disease</term>
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<term>Parkinson Disease</term>
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<term>Blotting, Western</term>
<term>Chromosomes, Artificial, Bacterial</term>
<term>Disease Models, Animal</term>
<term>Humans</term>
<term>Immunohistochemistry</term>
<term>Leucine-Rich Repeat Serine-Threonine Protein Kinase-2</term>
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<front><div type="abstract" xml:lang="en">Germline silencing of the PD-related protein LRRK2 does not alter glutamate or dopamine release in adult mice, but some exploratory abnormalities have been reported with ageing. Contrastingly, high levels of human LRRK2 cause locomotor alterations and cognitive deficits accompanied by reduced striatal dopamine levels, with the latter also observed in G2019S mutant mice. Comparative cognitive and motor behavioral testing of LRRK2 KO, overexpressor and mutant overexpressor mice has not previously been reported.</div>
</front>
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<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26282470</PMID>
<DateCreated><Year>2015</Year>
<Month>09</Month>
<Day>28</Day>
</DateCreated>
<DateCompleted><Year>2016</Year>
<Month>08</Month>
<Day>04</Day>
</DateCompleted>
<DateRevised><Year>2016</Year>
<Month>11</Month>
<Day>25</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1873-5126</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>21</Volume>
<Issue>10</Issue>
<PubDate><Year>2015</Year>
<Month>Oct</Month>
</PubDate>
</JournalIssue>
<Title>Parkinsonism & related disorders</Title>
<ISOAbbreviation>Parkinsonism Relat. Disord.</ISOAbbreviation>
</Journal>
<ArticleTitle>Chronic and acute LRRK2 silencing has no long-term behavioral effects, whereas wild-type and mutant LRRK2 overexpression induce motor and cognitive deficits and altered regulation of dopamine release.</ArticleTitle>
<Pagination><MedlinePgn>1156-63</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1016/j.parkreldis.2015.07.025</ELocationID>
<ELocationID EIdType="pii" ValidYN="Y">S1353-8020(15)00316-8</ELocationID>
<Abstract><AbstractText Label="INTRODUCTION" NlmCategory="BACKGROUND">Germline silencing of the PD-related protein LRRK2 does not alter glutamate or dopamine release in adult mice, but some exploratory abnormalities have been reported with ageing. Contrastingly, high levels of human LRRK2 cause locomotor alterations and cognitive deficits accompanied by reduced striatal dopamine levels, with the latter also observed in G2019S mutant mice. Comparative cognitive and motor behavioral testing of LRRK2 KO, overexpressor and mutant overexpressor mice has not previously been reported.</AbstractText>
<AbstractText Label="METHODS" NlmCategory="METHODS">Parallel, comparative behavioral characterization was performed assessing motor and cognitive abilities. Striatal antisense oligonucleotide injections were conducted to investigate the effects of acute LRRK2 silencing on behavior and dopamine fiber density. Striatal synaptosomes prepared from hG2019S mice assessed vesicular release of dopamine and its sensitivity to D2 autoreceptor stimulation.</AbstractText>
<AbstractText Label="RESULTS" NlmCategory="RESULTS">Genetic ablation of LRRK2 has no long-term consequences on motor or cognitive function. Consistently, no effects on behavior or dopaminergic fiber density were observed following acute striatal silencing. Conversely, 12-month OE mice show persistent locomotor deficits and worsening of cognitive abilities; whereas, hG2019S mice display early hyperactivity and effective learning and memory that progress to decreased motor and cognitive deficits at older ages. The G2019S mutation does not affect vesicular dopamine release, but decreases its sensitivity to D2-mediated inhibition.</AbstractText>
<AbstractText Label="CONCLUSION" NlmCategory="CONCLUSIONS">LRRK2 silencing is well tolerated in mouse, arguing PD does not result from LRRK2 loss of function. High levels of WT and G2019S LRRK2 produce similar but temporally distinct phenotypes, potentially modeling different stages of disease progression. The data implicate gain of LRRK2 function in the pathogenesis of PD.</AbstractText>
<CopyrightInformation>Copyright © 2015 Elsevier Ltd. All rights reserved.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Volta</LastName>
<ForeName>Mattia</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Centre for Applied Neurogenetics, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Cataldi</LastName>
<ForeName>Stefano</ForeName>
<Initials>S</Initials>
<AffiliationInfo><Affiliation>Centre for Applied Neurogenetics, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Beccano-Kelly</LastName>
<ForeName>Dayne</ForeName>
<Initials>D</Initials>
<AffiliationInfo><Affiliation>Centre for Applied Neurogenetics, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Munsie</LastName>
<ForeName>Lise</ForeName>
<Initials>L</Initials>
<AffiliationInfo><Affiliation>Centre for Applied Neurogenetics, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Tatarnikov</LastName>
<ForeName>Igor</ForeName>
<Initials>I</Initials>
<AffiliationInfo><Affiliation>Centre for Applied Neurogenetics, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Chou</LastName>
<ForeName>Patrick</ForeName>
<Initials>P</Initials>
<AffiliationInfo><Affiliation>Centre for Applied Neurogenetics, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Bergeron</LastName>
<ForeName>Sabrina</ForeName>
<Initials>S</Initials>
<AffiliationInfo><Affiliation>Centre for Applied Neurogenetics, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Mitchell</LastName>
<ForeName>Emma</ForeName>
<Initials>E</Initials>
<AffiliationInfo><Affiliation>Centre for Applied Neurogenetics, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Lim</LastName>
<ForeName>Roscoe</ForeName>
<Initials>R</Initials>
<AffiliationInfo><Affiliation>Centre for Applied Neurogenetics, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Khinda</LastName>
<ForeName>Jaskaran</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Centre for Applied Neurogenetics, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Lloret</LastName>
<ForeName>Alejandro</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Isis Pharmaceuticals Inc, 2855 Gazelle Court, Carlsbad, CA 92010, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Bennett</LastName>
<ForeName>C Frank</ForeName>
<Initials>CF</Initials>
<AffiliationInfo><Affiliation>Isis Pharmaceuticals Inc, 2855 Gazelle Court, Carlsbad, CA 92010, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Paradiso</LastName>
<ForeName>Carmela</ForeName>
<Initials>C</Initials>
<AffiliationInfo><Affiliation>Dept. of Medical Sciences, Section of Pharmacology, University of Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Morari</LastName>
<ForeName>Michele</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Dept. of Medical Sciences, Section of Pharmacology, University of Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Farrer</LastName>
<ForeName>Matthew J</ForeName>
<Initials>MJ</Initials>
<AffiliationInfo><Affiliation>Centre for Applied Neurogenetics, Canada. Electronic address: mfarrer@can.ubc.ca.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Milnerwood</LastName>
<ForeName>Austen J</ForeName>
<Initials>AJ</Initials>
<AffiliationInfo><Affiliation>Centre for Applied Neurogenetics, Canada; Division of Neurology, University of British Columbia, 2215 Wesbrook Mall, Vancouver V6T 1Z3, BC, Canada. Electronic address: amilnerwood@gmail.com.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
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<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2015</Year>
<Month>08</Month>
<Day>01</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>England</Country>
<MedlineTA>Parkinsonism Relat Disord</MedlineTA>
<NlmUniqueID>9513583</NlmUniqueID>
<ISSNLinking>1353-8020</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><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 2.7.11.1</RegistryNumber>
<NameOfSubstance UI="D017346">Protein-Serine-Threonine Kinases</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>VTD58H1Z2X</RegistryNumber>
<NameOfSubstance UI="D004298">Dopamine</NameOfSubstance>
</Chemical>
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<CitationSubset>IM</CitationSubset>
<MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D015153" MajorTopicYN="N">Blotting, Western</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D022202" MajorTopicYN="N">Chromosomes, Artificial, Bacterial</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D003072" MajorTopicYN="N">Cognition Disorders</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName>
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<MeshHeading><DescriptorName UI="D003342" MajorTopicYN="N">Corpus Striatum</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D004195" MajorTopicYN="N">Disease Models, Animal</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D004298" MajorTopicYN="N">Dopamine</DescriptorName>
<QualifierName UI="Q000557" MajorTopicYN="Y">secretion</QualifierName>
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<MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D007150" MajorTopicYN="N">Immunohistochemistry</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000071158" MajorTopicYN="N">Leucine-Rich Repeat Serine-Threonine Protein Kinase-2</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008810" MajorTopicYN="N">Mice, Inbred C57BL</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008822" MajorTopicYN="N">Mice, Transgenic</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D009043" MajorTopicYN="N">Motor Activity</DescriptorName>
<QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D010300" MajorTopicYN="N">Parkinson Disease</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D017346" MajorTopicYN="N">Protein-Serine-Threonine Kinases</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName>
</MeshHeading>
</MeshHeadingList>
<KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Behavior</Keyword>
<Keyword MajorTopicYN="N">Cognition</Keyword>
<Keyword MajorTopicYN="N">Genetic models</Keyword>
<Keyword MajorTopicYN="N">LRRK2</Keyword>
<Keyword MajorTopicYN="N">Parkinson's disease</Keyword>
<Keyword MajorTopicYN="N">Synaptosomes</Keyword>
</KeywordList>
</MedlineCitation>
<PubmedData><History><PubMedPubDate PubStatus="received"><Year>2015</Year>
<Month>04</Month>
<Day>30</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="revised"><Year>2015</Year>
<Month>07</Month>
<Day>23</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="accepted"><Year>2015</Year>
<Month>07</Month>
<Day>30</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="entrez"><Year>2015</Year>
<Month>8</Month>
<Day>19</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="pubmed"><Year>2015</Year>
<Month>8</Month>
<Day>19</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="medline"><Year>2016</Year>
<Month>8</Month>
<Day>5</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
</History>
<PublicationStatus>ppublish</PublicationStatus>
<ArticleIdList><ArticleId IdType="pubmed">26282470</ArticleId>
<ArticleId IdType="pii">S1353-8020(15)00316-8</ArticleId>
<ArticleId IdType="doi">10.1016/j.parkreldis.2015.07.025</ArticleId>
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