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Table 4 Novel potential risk factors in FTD

From: Frontotemporal dementia: insights into the biological underpinnings of disease through gene co-expression network analysis

Novel potential risk factor Interactor of Function Topography Evidence
KHSRP MAPT, GRN involved in alternative pre-mRNA splicing and mRNA localization FCTX WGCNA + VisANT
SF3A1 GRN
CREBBP MAPT acetyltransferase involved in chromatin remodelling and transcriptional activation/regulation
MLL2 methyl-transferase involved in chromatin remodelling
SRCAP involved in transcriptional activation/regulation
HCFC1
MARK2 MAPT kinase involved in stabilizing the microtubules and tau’s phosphorylation FCTX, TCXT WGCNA + PPI
MARK4 FCTX
EP300 acetyltransferase involved in tau’s acetylation FCTX, TCXT
AKT1 kinase involved in growth factor-induced neuronal survival in the developing nervous system TCTX
ATN1 GRN transcriptional co-repressor factor FCTX
SGTA involved in neuronal apoptotic processes
CRKL oncogene pleiotropic in physiologic signalling FCTX, TCXT
TLE3 transcriptional co-repressor factor
CYBB HLA-DRA, CTSC critical component of the oxidase system of phagocytes FCTX WGCNA + VisANT
DOCK8 involved in neuronal development and immune cells shaping
HLA-DMA HLA-DRA transmembrane protein of intracellular vesicles involved in peptide loading of MHC class II molecules FCTX, TCXT WGCNA + PPI
HLA-DMB
CD74 chaperone involved in antigen presentation during immune response
COPB2 TMEM106B involved in Golgi budding and vesicular trafficking FCTX WGCNA + VisANT
SERINC1 involved in lipid biosynthesis in neurons at the ER level
NRD1 metalloprotease with potential neuropathogenic role
TTC37 protein-protein interactor with chaperone activity
CAND1 C9orf72, VCP involved in ubiquitin ligase network FCTX WGCNA + VisANT
PSMD12 C9orf72 subunit of a multi-catalytic proteinase complex
MYCBP2 C9orf72 E3 ubiquitin protein ligase (alias)
ATL1 C9orf72, VCP involved in axonal maintenance
UBQLN1 VCP ubiquitin-like protein which links the ubiquitination and proteasome machineries
APP C9orf72 cell surface receptor and transmembrane precursor protein cleaved by secretases into different peptides: some of these can bind to the acetyltransferase complex (APBB1/TIP60) to promote transcriptional activation; others form the protein basis of the amyloid plaques FCTX, TCTX WGCNA + PPI
ELAVL1 RNA-binding protein that contain several RNA recognition motifs, and selectively bind AU-rich elements (AREs) found in the 3' untranslated regions of mRNAs. AREs signal degradation of mRNAs as a means to regulate gene expression; the ELAVL family stabilizes ARE-containing mRNAs
EIF2B2 beta subunit of eukaryotic initiation factor-2B (EIF2B). EIF2B is involved in protein synthesis and exchanges GDP and GTP for its activation and deactivation FCTX
CUL2 VCP Cullins are a family of NEDD8 targets important in the stabilization and degradation of proteins FCTX, TCTX
UBQLN1 part of the ubiquitination machinery of the proteasome to affect in vivo protein degradation
NF1 negative regulator of the ras signal transduction pathway (control such processes as actin cytoskeletal integrity, proliferation, differentiation, cell adhesion, apoptosis and cell migration)
NIPSNAP1 family of proteins involved in vesicular transport FCTX
BTRC constitutes one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box) that function in phosphorylation-dependent ubiquitination FCTX, TCTX
ARFGEF2 plays an important role in intracellular vesicular trafficking; involved in Golgi transport FCTX
COPS3 kinase activity that phosphorylates regulators involved in signal transduction
PLAA activation of protein kinase C (PKC) and PKC-dependent responses (in response to inflammatory mediators and release during apoptosis)
CLTA part of structural component of the lattice-type cytoplasmic face of coated pits and vesicles which entrap specific macromolecules during receptor-mediated endocytosis with regulatory function
ANXA7 a membrane binding protein with diverse properties (voltage-sensitive calcium channel activity, ion selectivity and membrane fusion)
UBQLN1 UBQLN2 part of the ubiquitination machinery of the proteasome to affect in vivo protein degradation FCTX, TCTX
SEC23A suggested to play a role in the ER-Golgi protein trafficking
USP9X protein similar to ubiquitin-specific proteases
STAM mediates downstream signaling of cytokine receptors and also play a role in ER to Golgi trafficking
HSPA13 member of the heat shock protein 70 family and is found associated with microsomes. Members of this protein family play a role in the processing of cytosolic and secretory proteins, as well as in the removal of denatured or incorrectly-folded proteins
RAB11A OPTN involvedin constitutive, regulated secretory pathways and protein transport FCTX
RTN3 expressed in neuroendocrine tissues: interacts with and modulates the activity of beta-amyloid converting enzyme 1 (BACE1), and the production of amyloid-beta
  1. Each novel potential risk factor is listed along with the interacting FTD-gene(s). The evidence of interaction is primarily defined by our WGCNA data that assigned each transcript to a module containing one (or more) FTD-gene(s) in frontal and/or temporal cortex. The nomenclature (WGCNA + VisANT) indicates that the novel potential risk factor is chosen because of its hub status and its interaction with FTD-gene(s) based on topological overlap measure (TOM) > 0.10 (see also Figs. 2, 3, 4 and 5). The nomenclature (WGCNA + PPI) indicates that the novel potential risk factor is chosen based on nominal overlap between interactive transcript(s) and protein(s). The potential risk factors belonging to the latter category are bolded as an indication that the WGCNA + PPI combination could be a strong indicator for regional-specific impacted functional networks. The main known function(s) of each novel potential genetic and/or functional risk factor is included in the central column. FCTX = frontal cortex; TCTX = temporal cortex