Leucine-rich repeat kinase 2 and alternative splicing in Parkinson's disease.
Identifieur interne : 000D86 ( PubMed/Curation ); précédent : 000D85; suivant : 000D87Leucine-rich repeat kinase 2 and alternative splicing in Parkinson's disease.
Auteurs : David A. Elliott [Australie] ; Woojin S. Kim ; Sarsha Gorissen ; Glenda M. Halliday ; John B J. KwokSource :
- Movement disorders : official journal of the Movement Disorder Society [ 1531-8257 ] ; 2012.
English descriptors
- KwdEn :
- Aged, Aged, 80 and over, Alternative Splicing, Autopsy, DNA, Complementary (genetics), DNA-Binding Proteins (genetics), Exons (genetics), Female, Gene Dosage, Gene Expression (genetics), Humans, Male, Membrane Microdomains (genetics), Mutation, Parkinson Disease (genetics), Parkinson Disease (pathology), Protein-Serine-Threonine Kinases (genetics), Real-Time Polymerase Chain Reaction, alpha-Synuclein (genetics), tau Proteins (genetics).
- MESH :
- chemical , genetics : DNA, Complementary, DNA-Binding Proteins, Protein-Serine-Threonine Kinases, alpha-Synuclein, tau Proteins.
- genetics : Exons, Gene Expression, Membrane Microdomains, Parkinson Disease.
- pathology : Parkinson Disease.
- Aged, Aged, 80 and over, Alternative Splicing, Autopsy, Female, Gene Dosage, Humans, Male, Mutation, Real-Time Polymerase Chain Reaction.
Abstract
Mutations of the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson's disease (PD) and are associated with pleiomorphic neuropathology. We hypothesize that LRRK2 mediates its pathogenic effect through alternative splicing of neurodegeneration genes. Methods used in this study included western blotting analysis of subcellular protein fractions, exon-array analysis of RNA from cultured neuroblastoma cells transfected with LRRK2 expression vectors, and reverse-transcription polymerase chain reaction (RT-PCR) of RNA from cultured cells and postmortem tissue. Overexpression of the LRRK2 G2019S mutant resulted in a significant (2.6-fold; P = 0.020) decrease in nuclear transactive response DNA-binding protein 43 levels. Exon-array analyses revealed that wild-type LRRK2 had a significant effect on the expression of genes with nuclear (P < 10(-22) ) and cell-cycle functions (P < 10(-15) ). We replicated changes in gene expression in 30% of selected genes by quantitative RT-PCR. Overexpression of LRRK2 resulted in the altered splicing of two genes associated with PD, with an increased inclusion of exon 10 of microtubule-associated protein tau (1.7-fold; P = 0.001) and exon 5 of the alpha-synuclein (SNCA) gene (1.6-fold; P =0.005). Moreover, overexpression of LRRK2 (G2019S) and two mutant genes associated with neurodegeneration, TARDBP (M337V) and FUS (R521H), were associated with decreased inclusion out of the dystonin (DST) 1e precursor exons in SK-N-MC cells. Altered splicing of SNCA (1.9-fold; P < 0.001) and DST genes (log(2) 2.3-fold; P = 0.005) was observed in a cohort of PD, compared with neurologically healthy, brains. This suggests that aberrant RNA metabolism is an important contributor to idiopathic PD.
DOI: 10.1002/mds.25005
PubMed: 22528366
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Leucine-rich repeat kinase 2 and alternative splicing in Parkinson's disease.</title><author><name sortKey="Elliott, David A" sort="Elliott, David A" uniqKey="Elliott D" first="David A" last="Elliott">David A. Elliott</name><affiliation wicri:level="1"><nlm:affiliation>Neuroscience Research Australia, Barker St., Randwick, Sydney, NSW 2031, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Neuroscience Research Australia, Barker St., Randwick, Sydney, NSW 2031</wicri:regionArea></affiliation></author><author><name sortKey="Kim, Woojin S" sort="Kim, Woojin S" uniqKey="Kim W" first="Woojin S" last="Kim">Woojin S. Kim</name></author><author><name sortKey="Gorissen, Sarsha" sort="Gorissen, Sarsha" uniqKey="Gorissen S" first="Sarsha" last="Gorissen">Sarsha Gorissen</name></author><author><name sortKey="Halliday, Glenda M" sort="Halliday, Glenda M" uniqKey="Halliday G" first="Glenda M" last="Halliday">Glenda M. Halliday</name></author><author><name sortKey="Kwok, John B J" sort="Kwok, John B J" uniqKey="Kwok J" first="John B J" last="Kwok">John B J. 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Elliott</name><affiliation wicri:level="1"><nlm:affiliation>Neuroscience Research Australia, Barker St., Randwick, Sydney, NSW 2031, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Neuroscience Research Australia, Barker St., Randwick, Sydney, NSW 2031</wicri:regionArea></affiliation></author><author><name sortKey="Kim, Woojin S" sort="Kim, Woojin S" uniqKey="Kim W" first="Woojin S" last="Kim">Woojin S. Kim</name></author><author><name sortKey="Gorissen, Sarsha" sort="Gorissen, Sarsha" uniqKey="Gorissen S" first="Sarsha" last="Gorissen">Sarsha Gorissen</name></author><author><name sortKey="Halliday, Glenda M" sort="Halliday, Glenda M" uniqKey="Halliday G" first="Glenda M" last="Halliday">Glenda M. Halliday</name></author><author><name sortKey="Kwok, John B J" sort="Kwok, John B J" uniqKey="Kwok J" first="John B J" last="Kwok">John B J. Kwok</name></author></analytic><series><title level="j">Movement disorders : official journal of the Movement Disorder Society</title><idno type="eISSN">1531-8257</idno><imprint><date when="2012" type="published">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aged</term><term>Aged, 80 and over</term><term>Alternative Splicing</term><term>Autopsy</term><term>DNA, Complementary (genetics)</term><term>DNA-Binding Proteins (genetics)</term><term>Exons (genetics)</term><term>Female</term><term>Gene Dosage</term><term>Gene Expression (genetics)</term><term>Humans</term><term>Male</term><term>Membrane Microdomains (genetics)</term><term>Mutation</term><term>Parkinson Disease (genetics)</term><term>Parkinson Disease (pathology)</term><term>Protein-Serine-Threonine Kinases (genetics)</term><term>Real-Time Polymerase Chain Reaction</term><term>alpha-Synuclein (genetics)</term><term>tau Proteins (genetics)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>DNA, Complementary</term><term>DNA-Binding Proteins</term><term>Protein-Serine-Threonine Kinases</term><term>alpha-Synuclein</term><term>tau Proteins</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Exons</term><term>Gene Expression</term><term>Membrane Microdomains</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Aged</term><term>Aged, 80 and over</term><term>Alternative Splicing</term><term>Autopsy</term><term>Female</term><term>Gene Dosage</term><term>Humans</term><term>Male</term><term>Mutation</term><term>Real-Time Polymerase Chain Reaction</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Mutations of the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson's disease (PD) and are associated with pleiomorphic neuropathology. We hypothesize that LRRK2 mediates its pathogenic effect through alternative splicing of neurodegeneration genes. Methods used in this study included western blotting analysis of subcellular protein fractions, exon-array analysis of RNA from cultured neuroblastoma cells transfected with LRRK2 expression vectors, and reverse-transcription polymerase chain reaction (RT-PCR) of RNA from cultured cells and postmortem tissue. Overexpression of the LRRK2 G2019S mutant resulted in a significant (2.6-fold; P = 0.020) decrease in nuclear transactive response DNA-binding protein 43 levels. Exon-array analyses revealed that wild-type LRRK2 had a significant effect on the expression of genes with nuclear (P < 10(-22) ) and cell-cycle functions (P < 10(-15) ). We replicated changes in gene expression in 30% of selected genes by quantitative RT-PCR. Overexpression of LRRK2 resulted in the altered splicing of two genes associated with PD, with an increased inclusion of exon 10 of microtubule-associated protein tau (1.7-fold; P = 0.001) and exon 5 of the alpha-synuclein (SNCA) gene (1.6-fold; P =0.005). Moreover, overexpression of LRRK2 (G2019S) and two mutant genes associated with neurodegeneration, TARDBP (M337V) and FUS (R521H), were associated with decreased inclusion out of the dystonin (DST) 1e precursor exons in SK-N-MC cells. Altered splicing of SNCA (1.9-fold; P < 0.001) and DST genes (log(2) 2.3-fold; P = 0.005) was observed in a cohort of PD, compared with neurologically healthy, brains. This suggests that aberrant RNA metabolism is an important contributor to idiopathic PD.</div></front></TEI><pubmed><MedlineCitation Owner="NLM" Status="MEDLINE"><PMID Version="1">22528366</PMID><DateCreated><Year>2012</Year><Month>07</Month><Day>18</Day></DateCreated><DateCompleted><Year>2012</Year><Month>11</Month><Day>21</Day></DateCompleted><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1531-8257</ISSN><JournalIssue CitedMedium="Internet"><Volume>27</Volume><Issue>8</Issue><PubDate><Year>2012</Year><Month>Jul</Month></PubDate></JournalIssue><Title>Movement disorders : official journal of the Movement Disorder Society</Title><ISOAbbreviation>Mov. Disord.</ISOAbbreviation></Journal><ArticleTitle>Leucine-rich repeat kinase 2 and alternative splicing in Parkinson's disease.</ArticleTitle><Pagination><MedlinePgn>1004-11</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1002/mds.25005</ELocationID><Abstract><AbstractText>Mutations of the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson's disease (PD) and are associated with pleiomorphic neuropathology. We hypothesize that LRRK2 mediates its pathogenic effect through alternative splicing of neurodegeneration genes. Methods used in this study included western blotting analysis of subcellular protein fractions, exon-array analysis of RNA from cultured neuroblastoma cells transfected with LRRK2 expression vectors, and reverse-transcription polymerase chain reaction (RT-PCR) of RNA from cultured cells and postmortem tissue. Overexpression of the LRRK2 G2019S mutant resulted in a significant (2.6-fold; P = 0.020) decrease in nuclear transactive response DNA-binding protein 43 levels. Exon-array analyses revealed that wild-type LRRK2 had a significant effect on the expression of genes with nuclear (P < 10(-22) ) and cell-cycle functions (P < 10(-15) ). We replicated changes in gene expression in 30% of selected genes by quantitative RT-PCR. Overexpression of LRRK2 resulted in the altered splicing of two genes associated with PD, with an increased inclusion of exon 10 of microtubule-associated protein tau (1.7-fold; P = 0.001) and exon 5 of the alpha-synuclein (SNCA) gene (1.6-fold; P =0.005). Moreover, overexpression of LRRK2 (G2019S) and two mutant genes associated with neurodegeneration, TARDBP (M337V) and FUS (R521H), were associated with decreased inclusion out of the dystonin (DST) 1e precursor exons in SK-N-MC cells. Altered splicing of SNCA (1.9-fold; P < 0.001) and DST genes (log(2) 2.3-fold; P = 0.005) was observed in a cohort of PD, compared with neurologically healthy, brains. 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CompleteYN="Y"><Grant><GrantID>R24AA012725</GrantID><Acronym>AA</Acronym><Agency>NIAAA 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>2012</Year><Month>04</Month><Day>23</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Mov Disord</MedlineTA><NlmUniqueID>8610688</NlmUniqueID><ISSNLinking>0885-3185</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D018076">DNA, Complementary</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004268">DNA-Binding 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