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Extensive transcriptomic study emphasizes importance of vesicular transport in C9orf72 expansion carriers.
Dickson, Dennis W; Baker, Matthew C; Jackson, Jazmyne L; DeJesus-Hernandez, Mariely; Finch, NiCole A; Tian, Shulan; Heckman, Michael G; Pottier, Cyril; Gendron, Tania F; Murray, Melissa E; Ren, Yingxue; Reddy, Joseph S; Graff-Radford, Neill R; Boeve, Bradley F; Petersen, Ronald C; Knopman, David S; Josephs, Keith A; Petrucelli, Leonard; Oskarsson, Björn; Sheppard, John W; Asmann, Yan W; Rademakers, Rosa; van Blitterswijk, Marka.
Afiliação
  • Dickson DW; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
  • Baker MC; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
  • Jackson JL; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
  • DeJesus-Hernandez M; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
  • Finch NA; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
  • Tian S; Department of Health Sciences Research, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
  • Heckman MG; Division of Biomedical Statistics and Informatics, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
  • Pottier C; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
  • Gendron TF; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
  • Murray ME; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
  • Ren Y; Department of Health Sciences Research, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
  • Reddy JS; Department of Health Sciences Research, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
  • Graff-Radford NR; Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
  • Boeve BF; Department of Neurology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
  • Petersen RC; Department of Neurology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
  • Knopman DS; Department of Neurology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
  • Josephs KA; Department of Neurology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
  • Petrucelli L; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
  • Oskarsson B; Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
  • Sheppard JW; Gianforte School of Computing, Montana State University, 357 Barnard Hall, Bozeman, MT, 59717, USA.
  • Asmann YW; Department of Health Sciences Research, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
  • Rademakers R; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Rademakers.Rosa@mayo.edu.
  • van Blitterswijk M; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. VanBlitterswijk.Marka@mayo.edu.
Acta Neuropathol Commun ; 7(1): 150, 2019 10 08.
Article em En | MEDLINE | ID: mdl-31594549
ABSTRACT
The majority of the clinico-pathological variability observed in patients harboring a repeat expansion in the C9orf72-SMCR8 complex subunit (C9orf72) remains unexplained. This expansion, which represents the most common genetic cause of frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND), results in a loss of C9orf72 expression and the generation of RNA foci and dipeptide repeat (DPR) proteins. The C9orf72 protein itself plays a role in vesicular transport, serving as a guanine nucleotide exchange factor that regulates GTPases. To further elucidate the mechanisms underlying C9orf72-related diseases and to identify potential disease modifiers, we performed an extensive RNA sequencing study. We included individuals for whom frontal cortex tissue was available FTLD and FTLD/MND patients with (n = 34) or without (n = 44) an expanded C9orf72 repeat as well as control subjects (n = 24). In total, 6706 genes were differentially expressed between these groups (false discovery rate [FDR] < 0.05). The top gene was C9orf72 (FDR = 1.41E-14), which was roughly two-fold lower in C9orf72 expansion carriers than in (disease) controls. Co-expression analysis revealed groups of correlated genes (modules) that were enriched for processes such as protein folding, RNA splicing, synaptic signaling, metabolism, and Golgi vesicle transport. Within our cohort of C9orf72 expansion carriers, machine learning uncovered interesting candidates associated with clinico-pathological features, including age at onset (vascular endothelial growth factor A [VEGFA]), C9orf72 expansion size (cyclin dependent kinase like 1 [CDKL1]), DPR protein levels (eukaryotic elongation factor 2 kinase [EEF2K]), and survival after onset (small G protein signaling modulator 3 [SGSM3]). Given the fact that we detected a module involved in vesicular transport in addition to a GTPase activator (SGSM3) as a potential modifier, our findings seem to suggest that the presence of a C9orf72 repeat expansion might hamper vesicular transport and that genes affecting this process may modify the phenotype of C9orf72-linked diseases.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Expansão das Repetições de DNA / Redes Reguladoras de Genes / Transcriptoma / Proteína C9orf72 / Heterozigoto Tipo de estudo: Prognostic_studies Limite: Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Expansão das Repetições de DNA / Redes Reguladoras de Genes / Transcriptoma / Proteína C9orf72 / Heterozigoto Tipo de estudo: Prognostic_studies Limite: Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2019 Tipo de documento: Article