Modelling TDP-43 proteinopathy in Drosophila uncovers shared and neuron-specific targets across ALS and FTD relevant circuits

Table 1 Shared TDP-43 candidate mRNA targets, between mushroom body and motor neurons, identified in Drosophila and found to be transcriptionally altered in single neuronal nuclei from FTD patient brains

Human gene	Fly gene	HGNC ID	DIOPT score	Log2FC	FDR	Gene function	Association with neurodegenerative disease
GPC6	dlp	HGNC:4454	11	0.411254	0.000270	GPI anchored heparan sulfate proteoglycan	AD risk factor in two GWAS studies [116, 117]
ENC1	CG9426	HGNC:3345	4	0.354832	0.000002	Actin cytoskeleton associated	Candidate risk factor in progression from asymptomatic to symptomatic AD [108]
FRAS1	cv-2	HGNC:19185	3	0.350035	0.000000	Binds BMP receptor and HSPG	Component of extracellular matrix altered in AD brains [118]
GRIA4	Ir68a	HGNC:4574	3	0.319357	0.000075	Glutamate ionotropic receptor AMPA type subunit 1	De novo variants associated with ID [119]; upregulated in CSF fluid of ALS patients and negatively correlated with severity [120]
OPCML	DIP-alpha	HGNC:8143	8	− 0.307174	0.000000	Synaptic cell adhesion molecule	This class of proteins associated with AD [121]; LSAMP was identified in this paper as well
LSAMP	DIP-alpha	HGNC:6705	8	− 0.327900	0.000089	Adhesion molecule involved in neuronal growth and axonal targeting	Altered expression in FTD and AD [122, 121]
KCNH5	eag	HGNC:6254	12	− 0.329006	0.000181	Potassium channel	Mutations assocaited with seizure disorders [123]; Upregulated in chronic acive lesion of Multiple Sclerosis [124]
GABRG3	Rdl	HGNC:4088	3	− 0.475203	0.000000	GABA gated chloride channel	Downregulated in AD mouse model [125]; Linked to neurodegeneration via role as transcriptional target of the retinoic acid receptor RARβ [126]

DIOPT score—ortholog identifier tool [95]. Log2FC and FDR—differential expression data for human orthologs, identified in neuronal nuclei from FTD patient brains exhibiting the molecular signature of TDP-43 pathology [see Materials and Methods, and 94. Gene function and association with neurodegenerative disease, as shown

ISSN: 2051-5960