Extensive transcriptomic study emphasizes importance of vesicular transport in C9orf72 expansion carriers

Dennis W. Dickson, Matthew C. Baker, Jazmyne L. Jackson, Mariely Dejesus-Hernandez, Ni Cole 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. SheppardYan W. Asmann, Rosa Rademakers, Marka Van Blitterswijk

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number150
JournalActa Neuropathologica Communications
Volume7
Issue number1
DOIs
StatePublished - Oct 8 2019

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Frontotemporal Lobar Degeneration
Motor Neuron Disease
Monomeric GTP-Binding Proteins
Dipeptides
GTP Phosphohydrolase Activators
Elongation Factor 2 Kinase
CDC2 Protein Kinase
Genes
RNA Splicing
RNA Sequence Analysis
Guanine Nucleotide Exchange Factors
Transport Vesicles
Proteins
Gene Regulatory Networks
GTP Phosphohydrolases
Protein Folding
Frontal Lobe
Age of Onset
Vascular Endothelial Growth Factor A
RNA

Keywords

  • Amyotrophic lateral sclerosis
  • C9orf72
  • Frontotemporal dementia
  • Frontotemporal lobar degeneration
  • Machine learning
  • Motor neuron disease
  • Repeat expansion disorders
  • RNA sequencing
  • Transcriptomics
  • Vesicular transport

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

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, Ni Cole 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.

In: Acta Neuropathologica Communications, Vol. 7, No. 1, 150, 08.10.2019.

Research output: Contribution to journalArticle

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T1 - Extensive transcriptomic study emphasizes importance of vesicular transport in C9orf72 expansion carriers

AU - Dickson, Dennis W.

AU - Baker, Matthew C.

AU - Jackson, Jazmyne L.

AU - Dejesus-Hernandez, Mariely

AU - Finch, Ni Cole A.

AU - Tian, Shulan

AU - Heckman, Michael G.

AU - Pottier, Cyril

AU - Gendron, Tania F.

AU - Murray, Melissa E.

AU - Ren, Yingxue

AU - Reddy, Joseph S.

AU - Graff-Radford, Neill R.

AU - Boeve, Bradley F.

AU - Petersen, Ronald C.

AU - Knopman, David S.

AU - Josephs, Keith A.

AU - Petrucelli, Leonard

AU - Oskarsson, Björn

AU - Sheppard, John W.

AU - Asmann, Yan W.

AU - Rademakers, Rosa

AU - Van Blitterswijk, Marka

PY - 2019/10/8

Y1 - 2019/10/8

N2 - 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.

AB - 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.

KW - Amyotrophic lateral sclerosis

KW - C9orf72

KW - Frontotemporal dementia

KW - Frontotemporal lobar degeneration

KW - Machine learning

KW - Motor neuron disease

KW - Repeat expansion disorders

KW - RNA sequencing

KW - Transcriptomics

KW - Vesicular transport

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