Transgenic LRRK2 (R1441G) rats-a model for Parkinson disease?
Identifieur interne : 000501 ( PubMed/Curation ); précédent : 000500; suivant : 000502Transgenic LRRK2 (R1441G) rats-a model for Parkinson disease?
Auteurs : Komal T. Shaikh [Canada] ; Alvin Yang [Canada] ; Ekaterina Youshin [Canada] ; Susanne Schmid [Canada]Source :
- PeerJ ; 2015.
Abstract
Parkinson disease (PD) is the most common movement disorder, characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra. While the cause of this disease is largely unknown, a rare autosomal dominant familial form of PD is caused by a genetic mutation in the leucine-rich repeat kinase 2 (LRRK2) gene that presumably leads to a gain-of-function of LRRK2 kinase activity. Here, we explored the potential of over expression of this human gene in a new transgenic rat model to serve as an animal model for PD. Commercially available BAC transgenic rats expressing human LRRK2 with the familial PD mutation, R1441G, and their wild-type siblings were tested for deficits in motor function, sensorimotor gating, and higher cognitive function reminiscent of PD through the ages of 3, 6, 9 and 12 months. At 12 months of age, rats were exposed to intraperitoneal injections of the environmental toxin Paraquat or saline. Our results indicate that LRRK2 (R1441G) transgenic rats do not show signs of neurodegeneration and do not develop significant motor or cognitive deficits until the age of 16 months. In addition, LRRK2 (R1441G) transgenic rats did not show increased vulnerability to sub-toxic doses of Paraquat. Gene expression studies indicate that despite genomic presence and initial expression of the transgene, its expression was greatly reduced in our aged rats. We conclude that the transgenic LRRK2 (R1441G) rat is not a valid model for studying the pathology of PD and discuss this in relation to other transgenic rat models.
DOI: 10.7717/peerj.945
PubMed: 26020005
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Shaikh</name><affiliation wicri:level="1"><nlm:affiliation>Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON , Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON </wicri:regionArea></affiliation></author><author><name sortKey="Yang, Alvin" sort="Yang, Alvin" uniqKey="Yang A" first="Alvin" last="Yang">Alvin Yang</name><affiliation wicri:level="1"><nlm:affiliation>Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON , Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON </wicri:regionArea></affiliation></author><author><name sortKey="Youshin, Ekaterina" sort="Youshin, Ekaterina" uniqKey="Youshin E" first="Ekaterina" last="Youshin">Ekaterina Youshin</name><affiliation wicri:level="1"><nlm:affiliation>Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON , Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON </wicri:regionArea></affiliation></author><author><name sortKey="Schmid, Susanne" sort="Schmid, Susanne" uniqKey="Schmid S" first="Susanne" last="Schmid">Susanne Schmid</name><affiliation wicri:level="1"><nlm:affiliation>Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON , Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON </wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2015">2015</date><idno type="RBID">pubmed:26020005</idno><idno type="pmid">26020005</idno><idno type="doi">10.7717/peerj.945</idno><idno type="wicri:Area/PubMed/Corpus">000501</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000501</idno><idno type="wicri:Area/PubMed/Curation">000501</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000501</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Transgenic LRRK2 (R1441G) rats-a model for Parkinson disease?</title><author><name sortKey="Shaikh, Komal T" sort="Shaikh, Komal T" uniqKey="Shaikh K" first="Komal T" last="Shaikh">Komal T. Shaikh</name><affiliation wicri:level="1"><nlm:affiliation>Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON , Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON </wicri:regionArea></affiliation></author><author><name sortKey="Yang, Alvin" sort="Yang, Alvin" uniqKey="Yang A" first="Alvin" last="Yang">Alvin Yang</name><affiliation wicri:level="1"><nlm:affiliation>Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON , Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON </wicri:regionArea></affiliation></author><author><name sortKey="Youshin, Ekaterina" sort="Youshin, Ekaterina" uniqKey="Youshin E" first="Ekaterina" last="Youshin">Ekaterina Youshin</name><affiliation wicri:level="1"><nlm:affiliation>Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON , Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON </wicri:regionArea></affiliation></author><author><name sortKey="Schmid, Susanne" sort="Schmid, Susanne" uniqKey="Schmid S" first="Susanne" last="Schmid">Susanne Schmid</name><affiliation wicri:level="1"><nlm:affiliation>Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON , Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON </wicri:regionArea></affiliation></author></analytic><series><title level="j">PeerJ</title><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Parkinson disease (PD) is the most common movement disorder, characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra. While the cause of this disease is largely unknown, a rare autosomal dominant familial form of PD is caused by a genetic mutation in the leucine-rich repeat kinase 2 (LRRK2) gene that presumably leads to a gain-of-function of LRRK2 kinase activity. Here, we explored the potential of over expression of this human gene in a new transgenic rat model to serve as an animal model for PD. Commercially available BAC transgenic rats expressing human LRRK2 with the familial PD mutation, R1441G, and their wild-type siblings were tested for deficits in motor function, sensorimotor gating, and higher cognitive function reminiscent of PD through the ages of 3, 6, 9 and 12 months. At 12 months of age, rats were exposed to intraperitoneal injections of the environmental toxin Paraquat or saline. Our results indicate that LRRK2 (R1441G) transgenic rats do not show signs of neurodegeneration and do not develop significant motor or cognitive deficits until the age of 16 months. In addition, LRRK2 (R1441G) transgenic rats did not show increased vulnerability to sub-toxic doses of Paraquat. Gene expression studies indicate that despite genomic presence and initial expression of the transgene, its expression was greatly reduced in our aged rats. We conclude that the transgenic LRRK2 (R1441G) rat is not a valid model for studying the pathology of PD and discuss this in relation to other transgenic rat models.</div></front></TEI><pubmed><MedlineCitation Status="PubMed-not-MEDLINE" Owner="NLM"><PMID Version="1">26020005</PMID><DateCreated><Year>2015</Year><Month>05</Month><Day>28</Day></DateCreated><DateCompleted><Year>2015</Year><Month>05</Month><Day>28</Day></DateCompleted><DateRevised><Year>2017</Year><Month>02</Month><Day>20</Day></DateRevised><Article PubModel="Electronic-eCollection"><Journal><JournalIssue CitedMedium="Print"><Volume>3</Volume><PubDate><Year>2015</Year></PubDate></JournalIssue><Title>PeerJ</Title><ISOAbbreviation>PeerJ</ISOAbbreviation></Journal><ArticleTitle>Transgenic LRRK2 (R1441G) rats-a model for Parkinson disease?</ArticleTitle><Pagination><MedlinePgn>e945</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.7717/peerj.945</ELocationID><Abstract><AbstractText>Parkinson disease (PD) is the most common movement disorder, characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra. While the cause of this disease is largely unknown, a rare autosomal dominant familial form of PD is caused by a genetic mutation in the leucine-rich repeat kinase 2 (LRRK2) gene that presumably leads to a gain-of-function of LRRK2 kinase activity. Here, we explored the potential of over expression of this human gene in a new transgenic rat model to serve as an animal model for PD. Commercially available BAC transgenic rats expressing human LRRK2 with the familial PD mutation, R1441G, and their wild-type siblings were tested for deficits in motor function, sensorimotor gating, and higher cognitive function reminiscent of PD through the ages of 3, 6, 9 and 12 months. At 12 months of age, rats were exposed to intraperitoneal injections of the environmental toxin Paraquat or saline. Our results indicate that LRRK2 (R1441G) transgenic rats do not show signs of neurodegeneration and do not develop significant motor or cognitive deficits until the age of 16 months. In addition, LRRK2 (R1441G) transgenic rats did not show increased vulnerability to sub-toxic doses of Paraquat. Gene expression studies indicate that despite genomic presence and initial expression of the transgene, its expression was greatly reduced in our aged rats. We conclude that the transgenic LRRK2 (R1441G) rat is not a valid model for studying the pathology of PD and discuss this in relation to other transgenic rat models.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Shaikh</LastName><ForeName>Komal T</ForeName><Initials>KT</Initials><AffiliationInfo><Affiliation>Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON , Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yang</LastName><ForeName>Alvin</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON , Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Youshin</LastName><ForeName>Ekaterina</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON , Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schmid</LastName><ForeName>Susanne</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON , Canada.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2015</Year><Month>05</Month><Day>12</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>PeerJ</MedlineTA><NlmUniqueID>101603425</NlmUniqueID></MedlineJournalInfo><CommentsCorrectionsList><CommentsCorrections RefType="Cites"><RefSource>J Neurosci. 1995 May;15(5 Pt 2):3863-75</RefSource><PMID 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MajorTopicYN="N">Motor testing</Keyword><Keyword MajorTopicYN="N">Paraquat</Keyword><Keyword MajorTopicYN="N">Parkinson disease</Keyword><Keyword MajorTopicYN="N">Transgenic rat</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2015</Year><Month>01</Month><Day>21</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2015</Year><Month>04</Month><Day>18</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2015</Year><Month>5</Month><Day>29</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2015</Year><Month>5</Month><Day>29</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2015</Year><Month>5</Month><Day>29</Day><Hour>6</Hour><Minute>1</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">26020005</ArticleId><ArticleId 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