RESUMO
The human KIBRA gene has been linked to human cognition through a lead intronic single-nucleotide polymorphism (SNP; rs17070145) that is associated with episodic memory performance and the risk to develop Alzheimer's disease. However, it remains unknown how this relates to the function of the KIBRA protein. Here, we identified two common missense SNPs (rs3822660G/T [M734I], rs3822659T/G [S735A]) in exon 15 of the human KIBRA gene to affect cognitive performance, and to be in almost complete linkage disequilibrium with rs17070145. The identified SNPs encode variants of the KIBRA C2 domain with distinct Ca(2+) dependent binding preferences for monophosphorylated phosphatidylinositols likely due to differences in the dynamics and folding of the lipid-binding pocket. Our results further implicate the KIBRA protein in higher brain function and provide direction to the cellular pathways involved.
Assuntos
Cognição/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação de Sentido Incorreto/genética , Fosfatidilinositóis/metabolismo , Fosfoproteínas/genética , Éxons/genética , Éxons/fisiologia , Feminino , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Desequilíbrio de Ligação/genética , Desequilíbrio de Ligação/fisiologia , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/fisiologia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/fisiologia , Testes Neuropsicológicos , Fosfoproteínas/fisiologia , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
The rs17070145 polymorphism (C â T substitution, intron 9) of the KIBRA gene has recently been associated with episodic memory and cognitive flexibility. These findings were inconsistent across reports though, and largely lacked gene-gene or gene-environment interactions. The aim of the present study was to determine the impact of the rs17070145 polymorphism on clinically relevant cognitive domains and its interaction with the modifiers 'lifestyle' and 'cardiovascular risk factors'. Five-hundred forty-five elderly volunteers (mean age 64 years, ±7 years, 56% women) accomplished a comprehensive cognitive testing. Principal component analysis was used to reveal the internal structure of the data, rendering four composite scores: verbal memory, word fluency, executive function/psychomotor speed, and working memory. Lifestyle was assessed with a detailed questionnaire, age-associated risk factors by clinical interview and examination. There was no main effect of the rs17070145 genotype on any cognitive composite scores. However, we found worse performance in executive functions for T-allele carriers in the presence of arterial hypertension (ß=-0.365, p=0.0077 and 0.031 after Bonferroni correction). This association was further modified by gender, showing the strongest association in hypertensive females (ß=-0.500, p=0.0072 and 0.029 after Bonferroni correction). The effect of KIBRA on cognitive function seems to be complex and modified by gender and arterial hypertension.
Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Transtornos Cognitivos/epidemiologia , Transtornos Cognitivos/genética , Hipertensão/epidemiologia , Hipertensão/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fosfoproteínas/genética , Idoso , Cognição/fisiologia , Estudos de Coortes , Comorbidade/tendências , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The ability of the mammalian brain to store and recall information is based on synaptic plasticity due to constant remodeling of synaptic contacts. Although various classes of proteins such as neurotransmitter receptors, cytoskeletal components and protein kinases were already identified as modulators of memory formation, their specific interactions and crosstalks are still poorly understood. Genetic variants of the scaffolding protein KIBRA (kidney brain) a substrate of the memory-related protein kinase C zeta and component of the neuronal cytoskeleton, were recently shown to be associated with human memory performance. However, the function of KIBRA on the cellular and physiological level is still unclear. To gain more insights into the temporal and spatial expression of KIBRA, we performed in situ hybridization assays and immunohistological staining of human and rodent (rat) brain. Our data demonstrate that KIBRA is mainly expressed in memory-related regions of the brain (hippocampus, cortex) but is also found in the cerebellum and the hypothalamus. In primary hippocampal neurons, KIBRA displays a somatodendritic distribution and an enrichment at the postsynaptic density. Binding studies further show that KIBRA is able to form head-to-tail homodimers and that dimerization is mediated by the internal C2-like domain. Our data indicate that KIBRA is involved in brain development and memory formation as a postsynaptic scaffold protein connecting cytoskeletal and signaling molecules.
