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The genetic locus encoding KIBRA, a member of the WWC family of proteins, has recently been shown to be associated with human memory performance through genome-wide single nucleotide polymorphism screening. Gene expression analysis and a variety of functional studies have further indicated that such a role is biologically plausible for KIBRA. Here, we review the existing literature, illustrate connections between the different lines of evidence, and derive models based on KIBRA’s function(s) in the brain that can be further tested experimentally.
Introduction
To fully understand how the acquisition, maintenance and recall of memories is achieved is one of the holy grails of neuroscience. Since the definition of the g-factor for “general cognitive ability” over a century ago (Spearman, 1904) and the characterization of the landmark patient H.M. in 1957 (Scoville and Milner, 1957), the field of cognitive neuropsychology has been attempting to elucidate the brain structures and molecular players involved in these processes. However, most of this progress has been reached stepwise, working forward from brain structure to structure and molecule to molecule in a hypothesis-driven fashion (Lee and Silva, 2009). Recently, the advent of high-throughput genomic polymorphism scanning technologies has revolutionized our ability to search for the common genetic drivers of memory and other cognitive domains in a hypothesis-free manner (Goldberg and Weinberger, 2004; Fisher, 2006; Payton, 2006, 2009; Potkin et al., 2009). In the case of KIBRA (also known as WWC1 for WW and C2 domain containing 1), the topic of this review, evidence for a link to cognition occurred independently both from genetic association studies (Papassotiropoulos et al., 2006) and from biochemical work (Büther et al., 2004).
Beyond understanding the way memory works, one practical goal of studying genes with relation to cognitive performance is to identify new treatment strategies that cope with the various cognitive disabilities for which treatment options are urgently needed. The population aging in industrialized countries is expected to result in a strong increase in cognitive health problems in the next decades, both as a result of aging-associated cognitive decline, as well as increased prevalence of neuropsychiatric diseases such as Alzheimer’s disease. Here, novel discoveries in cognition are sought to broaden the spectrum of pharmacologically addressable targets and hypotheses. The KIBRA-pathway appears to present a novel promising inroad for this, since KIBRA has been both linked to normal cognitive performance and to Alzheimer’s disease.
Here, we highlight the most important functional aspects of KIBRA, and connect genetic and biochemical data to aid in the formation of hypotheses related to KIBRA’s cellular and molecular function.
The KIBRA Gene and Protein
KIBRA was first cloned and initially characterized by Kremerskothen et al. (2003) as a molecule that interacts with the postsynaptic protein dendrin. Human KIBRA, encoded by the WWC1 gene, is located on chromosome 5q35.1, and contains 1113 amino acids and has a predicted size or 125.3 kDa. From N- to C-terminus a number of known protein domains have been identified which are depicted in Figure 1. The WW-domains (aa 6–86), which cover a stretch of 35–40 amino acids contain two conserved tryptophan residues. These domains are responsible for the interaction with various proteins containing proline-rich sequences (PPxY). A putative nuclear localization signal was identified between amino acids 361–376 (Rayala et al., 2006). A C2 domain composed of two four-stranded β-sheets is located between amino acid 655 and 783. The 130 residues of the C2 domain are involved in binding phospholipids in a calcium-dependent manner. C2 domains are found in proteins with functions ranging from signal transduction to vesicular trafficking (Rizo and Sudhof, 1998). Calcium binding induces a change in the electrostatic potential, which enhances phospholipid binding. A glutamic acid-rich region is located between amino acids 845 and 873 (Kremerskothen et al., 2003; Rayala et al., 2006). Lastly, a putative class III PDZ-binding sequence has been identified between amino acids 1110 and 1113 (Duning et al., 2008).
[View Larger Version of this Image]
Figure 1. Structural features of the human KIBRA protein. Shown are the identified domains in the KIBRA protein. WW domains are located between position 6 and 86, and cover about 40 amino acids containing two conserved tryptophan residues. WW domains are generally thought to be responsible for the interaction with various proteins that contain proline-rich sequences such as PPxY. The C2 domain is located between amino acids 655 and 783. This is a conserved membrane targeting motif composed of β-sheets. The 130 residues of C2 are involved in binding phospholipids in a calcium-dependent manner. The PKCζ binding region is located at amino acids 953–996 and contains two serine residues that can be phosphorylated by the kinase. The last four amino acids contain a PDZ binding motif.
Human Genetic Evidence for KIBRA’s Role in Cognition
KIBRA has come into the focus of the neurogenetics field following the publication of human evidence pointing to an involvement of the gene in memory performance and cognition (Papassotiropoulos et al., 2006). In that publication, the authors report that carriers of the KIBRA/ WWC1 (rs17070145) T allele or, to a lesser extent, the calsyntenin 2 (CLSTN2) rs6439886 T allele performed significantly better on multiple episodic memory tasks than those homozygous for the C allele at either polymorphism. Furthermore, using functional magnetic resonance imaging (fMRI), they observed that brain activation (measured as oxygen extraction from blood) in key areas associated with memory retrieval was significantly greater in a selection of 15 WWC1 (rs17070145) T-allele-noncarriers than in 15 T-allele-carriers during an episodic memory task. After this initial finding, a considerable number of studies examined the WWC1 polymorphism in different contexts of cognition and in different populations (summarized in Table 1 and reviewed below).
[View Larger Version of this Table]
Table 1. Summary of the genetic association data available on the KIBRA polymorphism and memory and Alzheimer’s disease. Twelve studies that examine the KIBRA polymorphism in different populations are listed that were published before December 2009. Summarized are the citation and publication year, the population(s) examined, the study size, the effect(s) observed, and fi nally whether the study confi rmed the association of the rs17070145 SNP with memory performance.
A number of studies have examined the role of the rs17070145 polymorphism on the cognitive performance of non-demented individuals. The original finding was first confirmed in a small German cohort (n = 64) of healthy elderly individuals with a mean age of approximately 67 (Schaper et al., 2008). A second study also confirmed the influence of the T-allele on memory performance in a cohort of 312 elderly individuals between the ages of 50–89 (Almeida et al., 2008). Of note, 136 individuals in their study met diagnostic criteria for mild cognitive impairment (MCI) and they were able to identify an excess risk for MCI among non-T-allele-carriers, although it failed to reach statistical significance. A study on individuals with subjective memory complaints found that family history of dementia was significantly elevated in KIBRA non-T-allele-carriers while these same individuals exhibited better performance on verbal episodic memory tests (Nacmias et al., 2008).
In mid-2008 a report of non-replication of the influence of rs17070145 on episodic memory was published (Need et al., 2008). In this study the authors utilized two cohorts of European genetic origin. The first cohort (n = 300) was examined using a verbal recall memory test and the second cohort (n = 365) was phenotyped with the exact same auditory verbal learning test (AVLT) that was used in the original publication (Papassotiropoulos et al., 2006). The authors failed to see any association of rs17070145 with memory performance in either cohort although they reported to be well powered to do so. Additionally, some tagging SNPs within the KIBRA genetic locus were tested and no significant association signals could be identified following multiple testing corrections. In the concluding paragraph of this work the authors indicate that their non-replication findings are likely a good indicator of the challenges facing the study of the genetics of human memory and specifically point to the need for consistency in phenotyping across any replication efforts.
Finally, the largest replication effort was published in 2009 (Bates et al., 2009). In two cohorts numbering over 2,500 individuals combined, association between rs17070145 and memory performance was confirmed. Using the AVLT and the Wechsler Logical Memory Test, it was possible to demonstrate an association between rs17070145 T-allele-carrier status and item-distinctiveness storage and/or recollection. The authors suggest that KIBRA action is involved primarily in the conscious recall of item-based information and underscore the importance of attention to phenotyping when attempting to replicate a genetic association. The most recent study in healthy individuals replicated the positive effects of the KIBRA T-allele on episodic memory in a cohort of 383 individuals and showed that the effect size of the KIBRA polymorphism was modulated by the associative components of the task (Preuschhof et al., 2009). Additionally, this work suggests an interaction between KIBRA and CLSTN2 in episodic memory as the effect of carrying the rs17070145 T-allele was enhanced in carriers of the CLSTN2 rs6439886 C-allele.
Recently, KIBRA was also examined in the context of developmental or current exposure to nicotine (Jacobsen et al., 2009; Zhang et al., 2009). One study assessed association of SNP rs17070145 with verbal and visuospatial memory and fMRI changes in adolescents and could not find any significant influence of the polymorphisms either alone or in interaction with smoking habits or smoking exposure (Jacobsen et al., 2009). However, this study only examined 101 subjects with various combinations of prenatal and current nicotine exposure. The most recent study analyzed cognitive flexibility measures with the Wisconsin Card Sorting Test, ethnicity, and smoking habits in relation to the rs17070145 polymorphism (Zhang et al., 2009). In European Americans homozygous for the C-allele, an association with better cognitive flexibility was found. Curiously, current smokers of European origin with the T-allele performed significantly better than past smokers with the T-allele while there was no difference for C-allele carriers. There was no difference in performance in subjects of African American ethnicity. Association of the C instead of the T allele with better cognitive performance in different studies may be caused by differential effects of the polymorphism itself or yet unknown functional polymorphisms in the KIBRA gene in linkage disequilibrium with SNP rs17070145 on different domains of cognitive performance (e.g., more frontally located functions versus hippocampal functions).
KIBRA and Alzheimer’s Disease: Clues from the Genome and Transcriptome
Based on the associations with memory performance in healthy subjects, the link between KIBRA and Alzheimer’s disease was also examined. One study demonstrated that the rs17070145 C-allele was significantly associated with increased risk for developing late-onset AD (Corneveaux et al., 2008). However, another study showed that the T-allele was associated with an increased risk for very-late-onset AD (Rodriguez-Rodriguez et al., 2009). These differential findings may be reflective of differences in the genetic background of the studied samples, in the case/control selection criteria, or simply in the statistical power differences between the studies. A study in early 2009 also noted an association between KIBRA and late-onset AD risk (Beecham et al., 2009). Utilizing imputation to compare their data set generated on the Illumina HumanHap beadchip with data generated on a similar density Affymetrix array in a large AD study of 1,411 cases and controls (Reiman et al., 2007), the authors reported on a SNP located within KIBRA (rs12514426) that was associated [joint analysis p-value (uncorrected) = 0.000928] with late-onset AD. This SNP is in very low hypothetical linkage disequilibrium with rs17070145, but nonetheless represents a third independently reported genetic association between KIBRA and late-onset AD. Of note, the same analysis also yielded several hits in the SORL1 locus, a gene with strong biological and genetic links to Alzheimer’s disease (Andersen et al., 2005; Rogaeva et al., 2007; Dodson et al., 2008; Mayeux and Hyslop, 2008; Ma et al., 2009).
Two additional pieces of experimental evidence link KIBRA to AD (Corneveaux et al., 2008). First, the expression of KIBRA itself and the genes encoding several of its direct binding partners (DYNLL1, PRKCZ, SNX4, and KIAA0513) are significantly altered in non-tangle bearing neurons in key brain regions in AD patients versus matched controls. In neurons laser-dissected from the hippocampus, middle temporal gyrus, and posterior cingulate, KIBRA mRNA was found to be significantly increased between 2.4- and 3.0-fold, while in those same brain regions PKCζ mRNA was decreased by 2.3- to 3.3-fold. No significant changes were observed in the primary visual cortex, a region that is largely spared by AD pathology. Interestingly, only significant changes in PKCζ mRNA were detected in the hippocampus and middle temporal gyrus from patients with MCI (Huentelman lab communication, unpublished results), suggesting that perhaps the transcriptional alteration of these molecular species may follow a temporal pattern that could be related to dementia progression. Secondly, a link between rs17070145 T-allele carrier status and brain hypometabolism of fluorodeoxyglucose (FDG) as measured using positron emission tomography was described. It was shown that significant decreases in FDG uptake were noted in the precuneus and posterior/mid cingulate regions of neurologically normal individuals who were at elevated risk for developing AD. Some of these regions overlapped with previously identified hypometabolic changes in individuals stratified by APOE E4 carrier status (Reiman et al., 2004; Buckner et al., 2005; Reiman et al., 2005).
In conclusion, several pieces of evidence point to a link between KIBRA and Alzheimer’s disease. At present, the genetic link appears not as clear-cut as with memory performance in healthy individuals and therefore requires further replication. An interesting question is whether this link represents an extension or consequence of the involvement of KIBRA in episodic memory performance or possibly that it represents an independent function of KIBRA in the pathophysiology of Alzheimer’s disease.
Expression Patterns of KIBRA mRNA and Protein
KIBRA is predominately expressed in the kidney and brain in the adult organism. In the rodent and human brain, KIBRA is expressed in memory-related structures (including the hippocampus and cortex), the cerebellum, and in the hypothalamus (Johannsen et al., 2008). During brain development, expression has been shown to decrease from juvenile postnatal stages to the adult animal (Johannsen et al., 2008). On a subcellular level within neurons, KIBRA shows a somatodendritic staining pattern with enrichment in the perinuclear region and in postsynaptic structures. In subcellular fractionation experiments, KIBRA was heavily enriched in the postsynaptic density (PSD) fraction (Johannsen et al., 2008). However, nuclear localization has also been noted (Rayala et al., 2006). So far, it is unclear if different localizations are due to the type of cells investigated, experimental conditions, or possible modified variants of KIBRA.
Interacting Partners of KIBRA
KIBRA has been shown to participate in a number of cellular functions such as cell polarity and migration, vesicle transport, transcriptional regulation and synaptogenesis. Most hints to its function have come from the study of interaction partners identified in yeast two hybrid screens. To date, 10 direct interaction partners have been described (Figure 2). The two WW-domains, which cover a stretch of 35–40 amino acids containing two conserved tryptophan residues, appear responsible for many of the interactions with the identified proteins. The first interaction partner of KIBRA, identified by a yeast two hybrid screen, was the postsynaptic protein dendrin (KIAA0749) (Kremerskothen et al., 2003). Dendrin was first characterized as a dendritic protein whose expression is altered by sleep deprivation in the forebrain of rats (Neuner-Jehle et al., 1996). Dendrin is translated from a dendritically localized mRNA and interacts with alpha-actinin and the synaptic scaffolding molecule S-SCAM (Kremerskothen et al., 2006).
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