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. 2017 Jul;27(7):784-793.
doi: 10.1002/hipo.22731. Epub 2017 Apr 22.

Whole transcriptome profiling of the human hippocampus suggests an involvement of the KIBRA rs17070145 polymorphism in differential activation of the MAPK signaling pathway

Ignazio S Piras  1 , Jonida Krate  1 , Isabelle Schrauwen  1 , Jason J Corneveaux  1 , Geidy E Serrano  2 , Lucia Sue  2 , Thomas G Beach  2 , Matthew J Huentelman  1
Affiliations

Whole transcriptome profiling of the human hippocampus suggests an involvement of the KIBRA rs17070145 polymorphism in differential activation of the MAPK signaling pathway

Ignazio S Piras et al. Hippocampus. 2017 Jul.

Abstract

The rs17070145-T variant of the WWC1 gene, coding for the KIBRA protein, has been associated with both increased episodic memory performance and lowered risk for late onset Alzheimer's disease, although the mechanism behind this protective effect has not been completely elucidated. To achieve a better understanding of the pathways modulated by rs17070145 and its associated functional variant(s), we used laser capture microdissection (LCM) and RNA-sequencing to investigate the effect of rs17070145 genotypes on whole transcriptome expression in the human hippocampus (HP) of 22 neuropathologically normal individuals, with a specific focus on the dentate gyrus (DG) and at the pyramidal cells (PC) of CA1 and CA3 sub-regions. Differential expression analysis of RNA-seq data within the HP based on the rs17070145 genotype revealed an overexpression of genes involved in the MAPK signaling pathway, potentially driven by the T/T genotype. The most important contribution comes from genes dysregulated within the DG region. Other genes significantly dysregulated, and not involved in the MAPK pathway (Adj P < 0.01 and Fold Change > |1.00|) were: RSPO4 (HP); ARC, DUSP5, DNAJB5, EGR4, PPP1R15A, WBP11P1, EGR1, GADD45B (DG); CH25H, HSPA1A, HSPA1B, TNFSF9, and NPAS4 (PC). Several evidences suggested that the MAPK signaling pathway is linked with memory and learning processes. In non-neuronal cells, the KIBRA protein is phosphorylated by ERK1/2 (involved in the MAPK signaling) in cells as well as in vitro. Several of the other dysregulated genes are involved in memory and learning processes, as well as in Alzheimer's Disease. In conclusion, our results suggest that the effect of the WWC1 rs17070145 polymorphism on memory performance and Alzheimer's disease might be due to a differential regulation of the MAPK signaling, a key pathway involved in memory and learning processes.

Keywords: RNAseq; WWC1; dentate gyrus; memory; pyramidal cells.

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Figures

Figure 1
Figure 1
Expression levels of WWC1 gene in T/T and C/C rs17070145 carriers in HP, DG and PC (RNA sequencing data). Expression values are reported as normalized counts.
Figure 2
Figure 2
Expression levels of WWC1 in T/T and C/C rs17070145 carriers in HP and EC (qPCR data). Expression values are reported as expression rate of WWC1 versus the reference genes (2−ΔΔCT)
Figure 3
Figure 3
KEGG MAPK signaling pathway (KEGG ID: hs04010). The genes differentially expressed in HP, DG and PC are highlighted in grey.
See this image and copyright information in PMC

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