To further characterize the neuroprotective effects of PGRN, we performed a transcriptome analysis on the spinal cord from 50-day-old NTG, TDP-43(A315T) and TDP-43(A315T)xGRN mice (
n = 3 per group). The downregulation of endogenous mouse
Tardbp in TDP-43(A315T) mice was confirmed and this was not altered by PGRN overexpression (Additional file
1: Figure S2A). The expression of total
GRN RNA in the TDP-43(A315T)xGRN mice compared to endogenous mouse
Grn was estimated to be 2.36 (95% CI 1.00–3.72) (Additional file
1: Figure S2A). The samples clustered according to genotype (Additional file
1: Figure S2B) and a gene set enrichment analysis revealed especially reduced expression in ribosomal and mitochondrial genes in TDP-43(A315T) mice compared to NTG controls (Additional file
1: Table S1). PGRN overexpression particularly influenced extracellular matrix genes, but did not correct the reduced expression in ribosomal and mitochondrial genes. No changes in microglial or lysosomal genes were observed. There was a differential gene expression in 35 genes when comparing TDP-43(A315T) to NTG controls (Additional file
1: Table S2). For 7 of those genes, the expression was corrected by PGRN overexpression (Additional file
1: Figure S2C). A pathway analysis of these genes did not provide evidence for a protective effect of PGRN on one specific pathway, it rather hinted at a pleiotropic effect of PGRN on different pathways, some with possible importance for ALS-FTD (
Rsad2 is an ER stress-induced protein involved in cell defense,
Top2a is a topoisomerase involved in replication- and transcription-associated DNA breaks and repair,
Fbxo22 is part of the ubiquitin ligase complex involved in ubiquitination and degradation of proteins). Interestingly, using String DB, the proteins encoded by these 3 genes clustered in a protein-protein interaction network (Additional file
1: Figure S2D). The effect of PGRN on the expression of the key player, Rsad2, was confirmed using Western blot (Additional file
1: Figure S3). Although little is known about the concert function of these gene products, both
Rsad2 and
Fbxo22 are involved in the innate and adaptive immune system in the central nervous system and
Top2 is involved in inflammation-induced DNA damage [
43,
44].