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dc.contributor.authorAlmeida, Sandra
dc.contributor.authorGascon, Eduardo
dc.contributor.authorTran, Helene
dc.contributor.authorChou, Hsin-Jung
dc.contributor.authorGendron, Tania F.
dc.contributor.authorDeGroot, Steven R.
dc.contributor.authorTapper, Andrew R.
dc.contributor.authorSellier, Chantal
dc.contributor.authorCharlet-Berguerand, Nicolas
dc.contributor.authorKarydas, Anna
dc.contributor.authorSeeley, William W.
dc.contributor.authorBoxer, Adam L.
dc.contributor.authorPetrucelli, Leonard
dc.contributor.authorMiller, Bruce L.
dc.contributor.authorGao, Fen-Biao
dc.date2022-08-11T08:08:30.000
dc.date.accessioned2022-08-23T15:57:30Z
dc.date.available2022-08-23T15:57:30Z
dc.date.issued2013-09-01
dc.date.submitted2014-10-24
dc.identifier.citation<p>Acta Neuropathol. 2013 Sep;126(3):385-99. doi: 10.1007/s00401-013-1149-y. <a href="http://dx.doi.org/10.1007/s00401-013-1149-y">Link to article on publisher's site</a></p>
dc.identifier.issn0001-6322 (Linking)
dc.identifier.doi10.1007/s00401-013-1149-y
dc.identifier.pmid23836290
dc.identifier.urihttp://hdl.handle.net/20.500.14038/30214
dc.description<p>© The Author(s) 2013. Open Access. This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.</p>
dc.description.abstractThe recently identified GGGGCC repeat expansion in the noncoding region of C9ORF72 is the most common pathogenic mutation in patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). We generated a human neuronal model and investigated the pathological phenotypes of human neurons containing GGGGCC repeat expansions. Skin biopsies were obtained from two subjects who had > 1,000 GGGGCC repeats in C9ORF72 and their respective fibroblasts were used to generate multiple induced pluripotent stem cell (iPSC) lines. After extensive characterization, two iPSC lines from each subject were selected, differentiated into postmitotic neurons, and compared with control neurons to identify disease-relevant phenotypes. Expanded GGGGCC repeats exhibit instability during reprogramming and neuronal differentiation of iPSCs. RNA foci containing GGGGCC repeats were present in some iPSCs, iPSC-derived human neurons and primary fibroblasts. The percentage of cells with foci and the number of foci per cell appeared to be determined not simply by repeat length but also by other factors. These RNA foci do not seem to sequester several major RNA-binding proteins. Moreover, repeat-associated non-ATG (RAN) translation products were detected in human neurons with GGGGCC repeat expansions and these neurons showed significantly elevated p62 levels and increased sensitivity to cellular stress induced by autophagy inhibitors. Our findings demonstrate that key neuropathological features of FTD/ALS with GGGGCC repeat expansions can be recapitulated in iPSC-derived human neurons and also suggest that compromised autophagy function may represent a novel underlying pathogenic mechanism.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=23836290&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/
dc.subjectAmyotrophic Lateral Sclerosis
dc.subjectAnimals
dc.subjectCell Differentiation
dc.subjectDNA Repeat Expansion
dc.subjectFrontotemporal Dementia
dc.subjectGenotype
dc.subjectHumans
dc.subjectInduced Pluripotent Stem Cells
dc.subjectMice
dc.subjectMutation
dc.subjectNeurons
dc.subjectProteins
dc.subjectRNA-Binding Proteins
dc.subjectALS
dc.subjectAutophagy
dc.subjectC9ORF72
dc.subjectFTD
dc.subjectHexanucleotide repeats
dc.subjectiPSCs
dc.subjectNeurodegeneration
dc.subjectNeurons
dc.subjectp62
dc.subjectRAN translation
dc.subjectRNA foci
dc.subjectMedical Pathology
dc.subjectMolecular and Cellular Neuroscience
dc.subjectNervous System Diseases
dc.subjectNeurology
dc.subjectPathological Conditions, Signs and Symptoms
dc.subjectPsychiatry
dc.titleModeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons
dc.typeJournal Article
dc.source.journaltitleActa neuropathologica
dc.source.volume126
dc.source.issue3
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1461&amp;context=faculty_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/462
dc.identifier.contextkey6282118
refterms.dateFOA2022-08-23T15:57:31Z
html.description.abstract<p>The recently identified GGGGCC repeat expansion in the noncoding region of C9ORF72 is the most common pathogenic mutation in patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). We generated a human neuronal model and investigated the pathological phenotypes of human neurons containing GGGGCC repeat expansions. Skin biopsies were obtained from two subjects who had > 1,000 GGGGCC repeats in C9ORF72 and their respective fibroblasts were used to generate multiple induced pluripotent stem cell (iPSC) lines. After extensive characterization, two iPSC lines from each subject were selected, differentiated into postmitotic neurons, and compared with control neurons to identify disease-relevant phenotypes. Expanded GGGGCC repeats exhibit instability during reprogramming and neuronal differentiation of iPSCs. RNA foci containing GGGGCC repeats were present in some iPSCs, iPSC-derived human neurons and primary fibroblasts. The percentage of cells with foci and the number of foci per cell appeared to be determined not simply by repeat length but also by other factors. These RNA foci do not seem to sequester several major RNA-binding proteins. Moreover, repeat-associated non-ATG (RAN) translation products were detected in human neurons with GGGGCC repeat expansions and these neurons showed significantly elevated p62 levels and increased sensitivity to cellular stress induced by autophagy inhibitors. Our findings demonstrate that key neuropathological features of FTD/ALS with GGGGCC repeat expansions can be recapitulated in iPSC-derived human neurons and also suggest that compromised autophagy function may represent a novel underlying pathogenic mechanism.</p>
dc.identifier.submissionpathfaculty_pubs/462
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.contributor.departmentTapper Lab
dc.contributor.departmentDepartment of Psychiatry
dc.contributor.departmentDepartment of Neurology
dc.source.pages385-99
dc.contributor.studentSteven DeGroot
dc.description.thesisprogramNeuroscience


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