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

Ferrari, Raffaele; Forabosco, Paola; Vandrovcova, Jana; Botía, Juan A.; Guelfi, Sebastian; Warren, Jason D.; Momeni, Parastoo; Weale, Michael E.; Ryten, Mina; Hardy, John

doi:10.1186/s13024-016-0085-4

Molecular Neurodegeneration

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		involved in transcriptional activation/regulation
*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	FCTX
*CRKL*		oncogene pleiotropic in physiologic signalling	FCTX, TCXT
*TLE3*		transcriptional co-repressor factor	FCTX, TCXT
CYBB	HLA-DRA, CTSC	critical component of the oxidase system of phagocytes	FCTX	WGCNA + VisANT
DOCK8	HLA-DRA, CTSC	involved in neuronal development and immune cells shaping	FCTX	WGCNA + VisANT
*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	FCTX, TCTX
*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*	*OPTN*	expressed in neuroendocrine tissues: interacts with and modulates the activity of beta-amyloid converting enzyme 1 (BACE1), and the production of amyloid-beta	FCTX

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

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ISSN: 1750-1326

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