Neuropathology and Cellular Pathogenesis of Spinocerebellar Ataxia Type 12.
Identifieur interne : 000048 ( PubMed/Corpus ); précédent : 000047; suivant : 000049Neuropathology and Cellular Pathogenesis of Spinocerebellar Ataxia Type 12.
Auteurs : Elizabeth E. O'Hearn ; Hyon S. Hwang ; Susan E. Holmes ; Dobrila D. Rudnicki ; Daniel W. Chung ; Ana I. Seixas ; Rachael L. Cohen ; Christopher A. Ross ; John Q. Trojanowski ; Olga Pletnikova ; Juan C. Troncoso ; Russell L. MargolisSource :
- Movement disorders : official journal of the Movement Disorder Society [ 1531-8257 ] ; 2015.
Abstract
SCA12 is a progressive autosomal-dominant disorder, caused by a CAG/CTG repeat expansion in PPP2R2B on chromosome 5q32, and characterized by tremor, gait ataxia, hyperreflexia, dysmetria, abnormal eye movements, anxiety, depression, and sometimes cognitive impairment. Neuroimaging has demonstrated cerebellar and cortical atrophy. We now present the neuropathology of the first autopsied SCA12 brain and utilize cell models to characterize potential mechanisms of SCA12 neurodegeneration.
DOI: 10.1002/mds.26348
PubMed: 26340331
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Neuropathology and Cellular Pathogenesis of Spinocerebellar Ataxia Type 12.</title><author><name sortKey="O Hearn, Elizabeth E" sort="O Hearn, Elizabeth E" uniqKey="O Hearn E" first="Elizabeth E" last="O'Hearn">Elizabeth E. O'Hearn</name><affiliation><nlm:affiliation>Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Hwang, Hyon S" sort="Hwang, Hyon S" uniqKey="Hwang H" first="Hyon S" last="Hwang">Hyon S. Hwang</name><affiliation><nlm:affiliation>Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Holmes, Susan E" sort="Holmes, Susan E" uniqKey="Holmes S" first="Susan E" last="Holmes">Susan E. Holmes</name><affiliation><nlm:affiliation>Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Rudnicki, Dobrila D" sort="Rudnicki, Dobrila D" uniqKey="Rudnicki D" first="Dobrila D" last="Rudnicki">Dobrila D. Rudnicki</name><affiliation><nlm:affiliation>Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Chung, Daniel W" sort="Chung, Daniel W" uniqKey="Chung D" first="Daniel W" last="Chung">Daniel W. Chung</name><affiliation><nlm:affiliation>Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Seixas, Ana I" sort="Seixas, Ana I" uniqKey="Seixas A" first="Ana I" last="Seixas">Ana I. Seixas</name><affiliation><nlm:affiliation>Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Cohen, Rachael L" sort="Cohen, Rachael L" uniqKey="Cohen R" first="Rachael L" last="Cohen">Rachael L. Cohen</name><affiliation><nlm:affiliation>Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Ross, Christopher A" sort="Ross, Christopher A" uniqKey="Ross C" first="Christopher A" last="Ross">Christopher A. Ross</name><affiliation><nlm:affiliation>Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Trojanowski, John Q" sort="Trojanowski, John Q" uniqKey="Trojanowski J" first="John Q" last="Trojanowski">John Q. Trojanowski</name><affiliation><nlm:affiliation>Institute on Aging, Alzheimer's Disease Core Center, Udall Parkinson's Research Center, Center for Neurodegenerative Disease, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Pletnikova, Olga" sort="Pletnikova, Olga" uniqKey="Pletnikova O" first="Olga" last="Pletnikova">Olga Pletnikova</name><affiliation><nlm:affiliation>Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Troncoso, Juan C" sort="Troncoso, Juan C" uniqKey="Troncoso J" first="Juan C" last="Troncoso">Juan C. Troncoso</name><affiliation><nlm:affiliation>Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Margolis, Russell L" sort="Margolis, Russell L" uniqKey="Margolis R" first="Russell L" last="Margolis">Russell L. Margolis</name><affiliation><nlm:affiliation>Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2015">2015</date><idno type="doi">10.1002/mds.26348</idno><idno type="RBID">pubmed:26340331</idno><idno type="pmid">26340331</idno><idno type="wicri:Area/PubMed/Corpus">000048</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Neuropathology and Cellular Pathogenesis of Spinocerebellar Ataxia Type 12.</title><author><name sortKey="O Hearn, Elizabeth E" sort="O Hearn, Elizabeth E" uniqKey="O Hearn E" first="Elizabeth E" last="O'Hearn">Elizabeth E. O'Hearn</name><affiliation><nlm:affiliation>Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Hwang, Hyon S" sort="Hwang, Hyon S" uniqKey="Hwang H" first="Hyon S" last="Hwang">Hyon S. Hwang</name><affiliation><nlm:affiliation>Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Holmes, Susan E" sort="Holmes, Susan E" uniqKey="Holmes S" first="Susan E" last="Holmes">Susan E. Holmes</name><affiliation><nlm:affiliation>Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Rudnicki, Dobrila D" sort="Rudnicki, Dobrila D" uniqKey="Rudnicki D" first="Dobrila D" last="Rudnicki">Dobrila D. Rudnicki</name><affiliation><nlm:affiliation>Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Chung, Daniel W" sort="Chung, Daniel W" uniqKey="Chung D" first="Daniel W" last="Chung">Daniel W. Chung</name><affiliation><nlm:affiliation>Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Seixas, Ana I" sort="Seixas, Ana I" uniqKey="Seixas A" first="Ana I" last="Seixas">Ana I. Seixas</name><affiliation><nlm:affiliation>Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Cohen, Rachael L" sort="Cohen, Rachael L" uniqKey="Cohen R" first="Rachael L" last="Cohen">Rachael L. Cohen</name><affiliation><nlm:affiliation>Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Ross, Christopher A" sort="Ross, Christopher A" uniqKey="Ross C" first="Christopher A" last="Ross">Christopher A. Ross</name><affiliation><nlm:affiliation>Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Trojanowski, John Q" sort="Trojanowski, John Q" uniqKey="Trojanowski J" first="John Q" last="Trojanowski">John Q. Trojanowski</name><affiliation><nlm:affiliation>Institute on Aging, Alzheimer's Disease Core Center, Udall Parkinson's Research Center, Center for Neurodegenerative Disease, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Pletnikova, Olga" sort="Pletnikova, Olga" uniqKey="Pletnikova O" first="Olga" last="Pletnikova">Olga Pletnikova</name><affiliation><nlm:affiliation>Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Troncoso, Juan C" sort="Troncoso, Juan C" uniqKey="Troncoso J" first="Juan C" last="Troncoso">Juan C. Troncoso</name><affiliation><nlm:affiliation>Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Margolis, Russell L" sort="Margolis, Russell L" uniqKey="Margolis R" first="Russell L" last="Margolis">Russell L. Margolis</name><affiliation><nlm:affiliation>Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></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="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">SCA12 is a progressive autosomal-dominant disorder, caused by a CAG/CTG repeat expansion in PPP2R2B on chromosome 5q32, and characterized by tremor, gait ataxia, hyperreflexia, dysmetria, abnormal eye movements, anxiety, depression, and sometimes cognitive impairment. Neuroimaging has demonstrated cerebellar and cortical atrophy. We now present the neuropathology of the first autopsied SCA12 brain and utilize cell models to characterize potential mechanisms of SCA12 neurodegeneration.</div></front></TEI><pubmed><MedlineCitation Status="Publisher" Owner="NLM"><PMID Version="1">26340331</PMID><DateCreated><Year>2015</Year><Month>9</Month><Day>4</Day></DateCreated><DateRevised><Year>2015</Year><Month>9</Month><Day>30</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1531-8257</ISSN><JournalIssue CitedMedium="Internet"><PubDate><Year>2015</Year><Month>Sep</Month><Day>4</Day></PubDate></JournalIssue><Title>Movement disorders : official journal of the Movement Disorder Society</Title><ISOAbbreviation>Mov. Disord.</ISOAbbreviation></Journal><ArticleTitle>Neuropathology and Cellular Pathogenesis of Spinocerebellar Ataxia Type 12.</ArticleTitle><Pagination><MedlinePgn></MedlinePgn></Pagination><ELocationID EIdType="doi">10.1002/mds.26348</ELocationID><Abstract><AbstractText Label="OBJECTIVE" NlmCategory="OBJECTIVE">SCA12 is a progressive autosomal-dominant disorder, caused by a CAG/CTG repeat expansion in PPP2R2B on chromosome 5q32, and characterized by tremor, gait ataxia, hyperreflexia, dysmetria, abnormal eye movements, anxiety, depression, and sometimes cognitive impairment. Neuroimaging has demonstrated cerebellar and cortical atrophy. We now present the neuropathology of the first autopsied SCA12 brain and utilize cell models to characterize potential mechanisms of SCA12 neurodegeneration.</AbstractText><AbstractText Label="METHODS" NlmCategory="METHODS">A fixed SCA12 brain was examined using gross, microscopic, and immunohistochemical methods. The effect of the repeat expansion on PPP2R2B Bβ1 expression was examined in multiple cell types by transient transfection of constructs containing the PPP2R2B Bβ1 promoter region attached to a luciferase reporter. The neurotoxic effect of PPP2R2B overexpression was examined in transfected rat primary neurons.</AbstractText><AbstractText Label="RESULTS" NlmCategory="RESULTS">Neuropathological investigation revealed enlarged ventricles, marked cerebral cortical atrophy and Purkinje cell loss, less-prominent cerebellar and pontine atrophy, and neuronal intranuclear ubiquitin-positive inclusions, consistent with Marinesco bodies, which did not stain for long polyglutamine tracts, alpha-synuclein, tau, or transactive response DNA-binding protein 43. Reporter assays demonstrated that the region of PPP2R2B containing the repeat functions as a promoter, and that promoter activity increases with longer repeat length and is dependent on cell type, repeat sequence, and sequence flanking the repeat. Overexpression of PPP2R2B in primary cortical neurons disrupted normal morphology.</AbstractText><AbstractText Label="CONCLUSIONS" NlmCategory="CONCLUSIONS">SCA12 involves extensive, but selective, neurodegeneration distinct from Alzheimer's disease, synucleinopathies, tauopathies, and glutamine expansion diseases. SCA12 neuropathology may arise from the neurotoxic effect of repeat-expansion-induced overexpression of PPP2R2B. © 2015 International Parkinson and Movement Disorder Society.</AbstractText><CopyrightInformation>© 2015 Movement Disorder Society.</CopyrightInformation></Abstract><AuthorList><Author><LastName>O'Hearn</LastName><ForeName>Elizabeth E</ForeName><Initials>EE</Initials><AffiliationInfo><Affiliation>Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author><LastName>Hwang</LastName><ForeName>Hyon S</ForeName><Initials>HS</Initials><AffiliationInfo><Affiliation>Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author><LastName>Holmes</LastName><ForeName>Susan E</ForeName><Initials>SE</Initials><AffiliationInfo><Affiliation>Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author><LastName>Rudnicki</LastName><ForeName>Dobrila D</ForeName><Initials>DD</Initials><AffiliationInfo><Affiliation>Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author><LastName>Chung</LastName><ForeName>Daniel W</ForeName><Initials>DW</Initials><AffiliationInfo><Affiliation>Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author><LastName>Seixas</LastName><ForeName>Ana I</ForeName><Initials>AI</Initials><AffiliationInfo><Affiliation>Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Instituto de Biologia Molecular e Celular, Universidade do Porto, Oporto, Portugal.</Affiliation></AffiliationInfo></Author><Author><LastName>Cohen</LastName><ForeName>Rachael L</ForeName><Initials>RL</Initials><AffiliationInfo><Affiliation>Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author><LastName>Ross</LastName><ForeName>Christopher A</ForeName><Initials>CA</Initials><AffiliationInfo><Affiliation>Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Departments of Neuroscience and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author><LastName>Trojanowski</LastName><ForeName>John Q</ForeName><Initials>JQ</Initials><AffiliationInfo><Affiliation>Institute on Aging, Alzheimer's Disease Core Center, Udall Parkinson's Research Center, Center for Neurodegenerative Disease, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.</Affiliation></AffiliationInfo></Author><Author><LastName>Pletnikova</LastName><ForeName>Olga</ForeName><Initials>O</Initials><AffiliationInfo><Affiliation>Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author><LastName>Troncoso</LastName><ForeName>Juan C</ForeName><Initials>JC</Initials><AffiliationInfo><Affiliation>Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author><LastName>Margolis</LastName><ForeName>Russell L</ForeName><Initials>RL</Initials><AffiliationInfo><Affiliation>Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.</Affiliation></AffiliationInfo></Author></AuthorList><Language>ENG</Language><GrantList><Grant><GrantID>R01 NS064138</GrantID><Acronym>NS</Acronym><Agency>NINDS NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="">JOURNAL ARTICLE</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2015</Year><Month>9</Month><Day>4</Day></ArticleDate></Article><MedlineJournalInfo><MedlineTA>Mov Disord</MedlineTA><NlmUniqueID>8610688</NlmUniqueID><ISSNLinking>0885-3185</ISSNLinking></MedlineJournalInfo><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Purkinje</Keyword><Keyword MajorTopicYN="N">ataxia</Keyword><Keyword MajorTopicYN="N">neurodegeneration</Keyword><Keyword MajorTopicYN="N">promoter</Keyword><Keyword MajorTopicYN="N">spinocerebellar</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2015</Year><Month>5</Month><Day>6</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2015</Year><Month>6</Month><Day>16</Day></PubMedPubDate><PubMedPubDate 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