Extensive transcriptomic study emphasizes importance of vesicular transport in C9orf72 expansion carriers
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 neu...
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doaj-ab2960ee954841b5ba17d0dbe2ec19e52020-11-25T02:46:29ZengBMCActa Neuropathologica Communications2051-59602019-10-017112110.1186/s40478-019-0797-0Extensive transcriptomic study emphasizes importance of vesicular transport in C9orf72 expansion carriersDennis W. Dickson0Matthew C. Baker1Jazmyne L. Jackson2Mariely DeJesus-Hernandez3NiCole A. Finch4Shulan Tian5Michael G. Heckman6Cyril Pottier7Tania F. Gendron8Melissa E. Murray9Yingxue Ren10Joseph S. Reddy11Neill R. Graff-Radford12Bradley F. Boeve13Ronald C. Petersen14David S. Knopman15Keith A. Josephs16Leonard Petrucelli17Björn Oskarsson18John W. Sheppard19Yan W. Asmann20Rosa Rademakers21Marka van Blitterswijk22Department of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Health Sciences Research, Mayo ClinicDivision of Biomedical Statistics and Informatics, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Health Sciences Research, Mayo ClinicDepartment of Health Sciences Research, Mayo ClinicDepartment of Neurology, Mayo ClinicDepartment of Neurology, Mayo ClinicDepartment of Neurology, Mayo ClinicDepartment of Neurology, Mayo ClinicDepartment of Neurology, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neurology, Mayo ClinicGianforte School of Computing, Montana State UniversityDepartment of Health Sciences Research, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicAbstract 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.http://link.springer.com/article/10.1186/s40478-019-0797-0Frontotemporal dementiaFrontotemporal lobar degenerationAmyotrophic lateral sclerosisMotor neuron diseaseC9orf72Transcriptomics |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Dennis W. Dickson Matthew C. Baker Jazmyne L. Jackson Mariely DeJesus-Hernandez NiCole A. Finch Shulan Tian Michael G. Heckman Cyril Pottier Tania F. Gendron Melissa E. Murray Yingxue Ren Joseph S. Reddy Neill R. Graff-Radford Bradley F. Boeve Ronald C. Petersen David S. Knopman Keith A. Josephs Leonard Petrucelli Björn Oskarsson John W. Sheppard Yan W. Asmann Rosa Rademakers Marka van Blitterswijk |
spellingShingle |
Dennis W. Dickson Matthew C. Baker Jazmyne L. Jackson Mariely DeJesus-Hernandez NiCole A. Finch Shulan Tian Michael G. Heckman Cyril Pottier Tania F. Gendron Melissa E. Murray Yingxue Ren Joseph S. Reddy Neill R. Graff-Radford Bradley F. Boeve Ronald C. Petersen David S. Knopman Keith A. Josephs Leonard Petrucelli Björn Oskarsson John W. Sheppard Yan W. Asmann Rosa Rademakers Marka van Blitterswijk Extensive transcriptomic study emphasizes importance of vesicular transport in C9orf72 expansion carriers Acta Neuropathologica Communications Frontotemporal dementia Frontotemporal lobar degeneration Amyotrophic lateral sclerosis Motor neuron disease C9orf72 Transcriptomics |
author_facet |
Dennis W. Dickson Matthew C. Baker Jazmyne L. Jackson Mariely DeJesus-Hernandez NiCole A. Finch Shulan Tian Michael G. Heckman Cyril Pottier Tania F. Gendron Melissa E. Murray Yingxue Ren Joseph S. Reddy Neill R. Graff-Radford Bradley F. Boeve Ronald C. Petersen David S. Knopman Keith A. Josephs Leonard Petrucelli Björn Oskarsson John W. Sheppard Yan W. Asmann Rosa Rademakers Marka van Blitterswijk |
author_sort |
Dennis W. Dickson |
title |
Extensive transcriptomic study emphasizes importance of vesicular transport in C9orf72 expansion carriers |
title_short |
Extensive transcriptomic study emphasizes importance of vesicular transport in C9orf72 expansion carriers |
title_full |
Extensive transcriptomic study emphasizes importance of vesicular transport in C9orf72 expansion carriers |
title_fullStr |
Extensive transcriptomic study emphasizes importance of vesicular transport in C9orf72 expansion carriers |
title_full_unstemmed |
Extensive transcriptomic study emphasizes importance of vesicular transport in C9orf72 expansion carriers |
title_sort |
extensive transcriptomic study emphasizes importance of vesicular transport in c9orf72 expansion carriers |
publisher |
BMC |
series |
Acta Neuropathologica Communications |
issn |
2051-5960 |
publishDate |
2019-10-01 |
description |
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. |
topic |
Frontotemporal dementia Frontotemporal lobar degeneration Amyotrophic lateral sclerosis Motor neuron disease C9orf72 Transcriptomics |
url |
http://link.springer.com/article/10.1186/s40478-019-0797-0 |
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