title: Whole transcriptome profiling of the human hippocampus suggests an involvement of the KIBRA rs17070145 polymorphism in differential activation of the MAPK signaling pathway.
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.
authors.affiliation: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, 85004.
authors.forename: Ignazio S
authors.identifier: 0000-0003-0139-098X
authors.initials: IS
authors.lastname: Piras
authors.affiliation: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, 85004.
authors.forename: Jonida
authors.initials: J
authors.lastname: Krate
authors.affiliation: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, 85004.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Schrauwen
authors.affiliation: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, 85004.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Corneveaux
authors.affiliation: Civin Laboratory of Neuropathology at Banner Sun Health Research Institute, Sun City, Arizona, 85351.
authors.forename: Geidy E
authors.initials: GE
authors.lastname: Serrano
authors.affiliation: Civin Laboratory of Neuropathology at Banner Sun Health Research Institute, Sun City, Arizona, 85351.
authors.forename: Lucia
authors.initials: L
authors.lastname: Sue
authors.affiliation: Civin Laboratory of Neuropathology at Banner Sun Health Research Institute, Sun City, Arizona, 85351.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Beach
authors.affiliation: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, 85004.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005838:Genotype; D006624:Hippocampus; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008297:Male; D010750:Phosphoproteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; C513637:WWC1 protein, human
keywords: RNAseq; WWC1; dentate gyrus; memory; pyramidal cells