Please use this identifier to cite or link to this item: https://doi.org/10.1007/s00401-019-02045-5
DC FieldValue
dc.titleC9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy
dc.contributor.authorCali, Christopher P
dc.contributor.authorPatino, Maribel
dc.contributor.authorTai, Yee Kit
dc.contributor.authorHo, Wan Yun
dc.contributor.authorMcLean, Catriona A
dc.contributor.authorMorris, Christopher M
dc.contributor.authorSeeley, William W
dc.contributor.authorMiller, Bruce L
dc.contributor.authorGaig, Carles
dc.contributor.authorVonsattel, Jean Paul G
dc.contributor.authorWhite, Charles L
dc.contributor.authorRoeber, Sigrun
dc.contributor.authorKretzschmar, Hans
dc.contributor.authorTroncoso, Juan C
dc.contributor.authorTroakes, Claire
dc.contributor.authorGearing, Marla
dc.contributor.authorGhetti, Bernardino
dc.contributor.authorVan Deerlin, Vivianna M
dc.contributor.authorLee, Virginia M-Y
dc.contributor.authorTrojanowski, John Q
dc.contributor.authorMok, Kin Y
dc.contributor.authorLing, Helen
dc.contributor.authorDickson, Dennis W
dc.contributor.authorSchellenberg, Gerard D
dc.contributor.authorLing, Shuo-Chien
dc.contributor.authorLee, Edward B
dc.date.accessioned2021-11-10T06:28:35Z
dc.date.available2021-11-10T06:28:35Z
dc.date.issued2019-11-01
dc.identifier.citationCali, Christopher P, Patino, Maribel, Tai, Yee Kit, Ho, Wan Yun, McLean, Catriona A, Morris, Christopher M, Seeley, William W, Miller, Bruce L, Gaig, Carles, Vonsattel, Jean Paul G, White, Charles L, Roeber, Sigrun, Kretzschmar, Hans, Troncoso, Juan C, Troakes, Claire, Gearing, Marla, Ghetti, Bernardino, Van Deerlin, Vivianna M, Lee, Virginia M-Y, Trojanowski, John Q, Mok, Kin Y, Ling, Helen, Dickson, Dennis W, Schellenberg, Gerard D, Ling, Shuo-Chien, Lee, Edward B (2019-11-01). C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy. ACTA NEUROPATHOLOGICA 138 (5) : 795-811. ScholarBank@NUS Repository. https://doi.org/10.1007/s00401-019-02045-5
dc.identifier.issn00016322
dc.identifier.issn14320533
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/205790
dc.description.abstractMicrosatellite repeat expansion disease loci can exhibit pleiotropic clinical and biological effects depending on repeat length. Large expansions in C9orf72 (100s–1000s of units) are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). However, whether intermediate expansions also contribute to neurodegenerative disease is not well understood. Several studies have identified intermediate repeats in Parkinson’s disease patients, but the association was not found in autopsy-confirmed cases. We hypothesized that intermediate C9orf72 repeats are a genetic risk factor for corticobasal degeneration (CBD), a neurodegenerative disease that can be clinically similar to Parkinson’s but has distinct tau protein pathology. Indeed, intermediate C9orf72 repeats were significantly enriched in autopsy-proven CBD (n = 354 cases, odds ratio = 3.59, p = 0.00024). While large C9orf72 repeat expansions are known to decrease C9orf72 expression, intermediate C9orf72 repeats result in increased C9orf72 expression in human brain tissue and CRISPR/cas9 knockin iPSC-derived neural progenitor cells. In contrast to cases of FTD/ALS with large C9orf72 expansions, CBD with intermediate C9orf72 repeats was not associated with pathologic RNA foci or dipeptide repeat protein aggregates. Knock-in cells with intermediate repeats exhibit numerous changes in gene expression pathways relating to vesicle trafficking and autophagy. Additionally, overexpression of C9orf72 without the repeat expansion leads to defects in autophagy under nutrient starvation conditions. These results raise the possibility that therapeutic strategies to reduce C9orf72 expression may be beneficial for the treatment of CBD.
dc.language.isoen
dc.publisherSPRINGER
dc.sourceElements
dc.subjectScience & Technology
dc.subjectLife Sciences & Biomedicine
dc.subjectClinical Neurology
dc.subjectNeurosciences
dc.subjectPathology
dc.subjectNeurosciences & Neurology
dc.subjectNeurodegeneration
dc.subjectCorticobasal degeneration
dc.subjectC9orf72 repeat expansion
dc.subjectParkinsonism
dc.subjectAutophagy
dc.subjectGGGGCC-HEXANUCLEOTIDE REPEAT
dc.subjectFRONTOTEMPORAL DEMENTIA
dc.subjectPARKINSONS-DISEASE
dc.subjectLATERAL-SCLEROSIS
dc.subjectGENETIC CAUSE
dc.subjectEXPANSION
dc.subjectHYPERMETHYLATION
dc.subjectPROTEIN
dc.subjectALS
dc.subjectIDENTIFICATION
dc.typeArticle
dc.date.updated2021-11-10T01:17:03Z
dc.contributor.departmentPHYSIOLOGY
dc.contributor.departmentSURGERY
dc.description.doi10.1007/s00401-019-02045-5
dc.description.sourcetitleACTA NEUROPATHOLOGICA
dc.description.volume138
dc.description.issue5
dc.description.page795-811
dc.published.statePublished
Appears in Collections:Staff Publications
Elements

Show simple item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
Cali et al..pdf2.02 MBAdobe PDF

OPEN

Post-printView/Download

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.