Different gene expression profiles in iPSC-derived motor neurons from ALS8 patients with variable clinical courses suggest mitigating pathways for neurodegeneration

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dc.contributorLaboratório de Expressão Gênica em Eucariotospt_BR
dc.contributorLab. Parasitologiapt_BR
dc.contributor.authorOliveira, Danyllopt_BR
dc.contributor.authorVicente, David Abraham Moralespt_BR
dc.contributor.authorAmaral, Murilo Senapt_BR
dc.contributor.authorLuz, Liviapt_BR
dc.contributor.authorSertié, Andrea Lpt_BR
dc.contributor.authorLeite, Felipe Spt_BR
dc.contributor.authorNavarro, Claudiapt_BR
dc.contributor.authorKaid, Carolinipt_BR
dc.contributor.authorEsposito, Joycept_BR
dc.contributor.authorGoulart, Ernestopt_BR
dc.contributor.authorCaires, Luizpt_BR
dc.contributor.authorAlves, Luciana Mpt_BR
dc.contributor.authorMelo, Uirá Soutopt_BR
dc.contributor.authorFigueiredo, Thalitapt_BR
dc.contributor.authorOkamoto, Oswaldo K.pt_BR
dc.contributor.authorVerjovski-Almeida, Sergiopt_BR
dc.contributor.authorZatz, Mayanapt_BR
dc.date.accessioned2020-07-09T21:27:24Z-
dc.date.available2020-07-09T21:27:24Z-
dc.date.issued2020pt_BR
dc.identifier.citationOliveira D, Vicente DAM, Amaral MS, Luz L, Sertié AL, Leite FS, et al. Different gene expression profiles in iPSC-derived motor neurons from ALS8 patients with variable clinical courses suggest mitigating pathways for neurodegeneration. Hum. Mol. Genet.. 2020 Apr;29(9):1465-1475. doi:10.1093/hmg/ddaa069.pt_BR
dc.identifier.urihttps://repositorio.butantan.gov.br/handle/butantan/3007-
dc.description.abstractAmyotrophic Lateral Sclerosis type 8 (ALS8) is an autosomal dominant form of ALS, which is caused by pathogenic variants in the VAPB gene. Here we investigated five ALS8 patients, classified as ‘severe’ and ‘mild’ from a gigantic Brazilian kindred, carrying the same VAPB mutation but displaying different clinical courses. Copy Number Variation (CNV) and Whole Exome Sequencing (WES) analyses in such individuals ruled out previously described genetic modifiers of pathogenicity. After deriving induced pluripotent stem cells (iPSCs) for each patient (N=5) and controls (N=3), motor neurons were differentiated, and high-throughput RNA-Seq gene expression measurements were performed. Functional cell death and oxidative metabolism assays were also carried out in patients’ iPSC-derived motor neurons. The degree of cell death and mitochondrial oxidative metabolism were similar in iPSC-derived motor neurons from mild patients and controls, and were distinct from those of severe patients. Similar findings were obtained when RNA-Seq from such cells was performed. Overall, 43 genes were upregulated and 66 downregulated in the two mild ALS8 patients when compared with severe ALS8 individuals and controls. Interestingly, significantly enriched pathways found among differentially expressed genes, such as protein translation and protein targeting to endoplasmic reticulum (ER), are known to be associated with neurodegenerative processes. Taken together, the mitigating mechanisms here presented appear to maintain motor neuron survival by keeping translational activity and protein targeting to ER in such cells. As ALS8 physiopathology has been associated with proteostasis mechanisms in ER–mitochondria contact sites, such differentially expressed genes appear to relate to the bypass of VAPB deficiency.pt_BR
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)pt_BR
dc.description.sponsorshipInstitutos Nacionais de Ciência e Tecnologia (INCTs)pt_BR
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)pt_BR
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)pt_BR
dc.format.extent1465-1475pt_BR
dc.language.isoEnglishpt_BR
dc.relation.ispartofHuman Molecular Geneticspt_BR
dc.rightsOpen Accesspt_BR
dc.titleDifferent gene expression profiles in iPSC-derived motor neurons from ALS8 patients with variable clinical courses suggest mitigating pathways for neurodegenerationpt_BR
dc.typeArticlept_BR
dc.identifier.doi10.1093/hmg/ddaa069pt_BR
dc.identifier.urlhttps://doi.org/10.1093/hmg/ddaa069pt_BR
dc.contributor.externalUniversidade de São Paulo (USP)¦¦Brasilpt_BR
dc.contributor.externalHospital Israelita Albert Einstein¦¦Brasilpt_BR
dc.contributor.externalUniversidade Estadual de Campinas (UNICAMP)¦¦Brasilpt_BR
dc.contributor.externalUniversidade Federal de Alagoas (UFAL)¦¦Brasilpt_BR
dc.identifier.citationvolume29pt_BR
dc.identifier.citationissue9pt_BR
dc.relation.ispartofabbreviatedHum Mol Genetpt_BR
dc.identifier.citationabntv. 29, n. 9, p. 1465-1475, abr. 2020pt_BR
dc.identifier.citationvancouver2020 Apr;29(9):1465-1475pt_BR
dc.contributor.butantanVicente, David Abraham Morales|:Aluno|:Laboratório de Expressão Gênica em Eucariotos|:pt_BR
dc.contributor.butantanAmaral, Murilo Sena|:Técnico|:Laboratório de Expressão Gênica em Eucariotos|:pt_BR
dc.contributor.butantanVerjovski-Almeida, Sergio|:Pesquisador|:Laboratório de Expressão Gênica em Eucariotos|:Autor de correspondênciapt_BR
dc.sponsorship.butantanConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)¦¦pt_BR
dc.sponsorship.butantanCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)¦¦001pt_BR
dc.sponsorship.butantanFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)¦¦2015/14821-1pt_BR
dc.sponsorship.butantanFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)¦¦2017/16283-2pt_BR
dc.sponsorship.butantanFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)¦¦2013/08028-1pt_BR
dc.sponsorship.butantanFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)¦¦2014/50931-3pt_BR
dc.sponsorship.butantanFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)¦¦465355/2014-5.pt_BR
dc.sponsorship.butantanInstitutos Nacionais de Ciência e Tecnologia (INCTs)¦¦465355/2014-5pt_BR
dc.identifier.bvsccBR78.1pt_BR
dc.identifier.bvsdbIBProdpt_BR
dc.description.dbindexedYespt_BR
item.openairetypeArticle-
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item.grantfulltextembargo_29990101-
item.languageiso639-1English-
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