Aggregated proteins in schizophrenia and other chronic mental diseases: DISC1opathies

Chronic mental diseases (CMD) like the schizophrenias are progressive diseases of heterogenous but poorly understood biological origin. An imbalance in proteostasis is a hallmark of dysfunctional neurons, leading to impaired clearance and abnormal deposition of protein aggregates. Thus, it can be hypothesized that unbalanced proteostasis in such neurons may also lead to protein aggregates in schizophrenia. These protein aggregates, however, would be more subtle then in the classical neurodegenerative diseases and as such have not yet been detected. The DISC1 (Disrupted-in-schizophrenia 1) gene is considered among the most promising candidate genes for CMD having been identified as linked to CMD in a Scottish pedigree and having since been found to associate to various phenotypes of CMD. We have recently demonstrated increased insoluble DISC1 protein in the cingular cortex in approximately 20% of cases of CMD within the widely used Stanley Medical Research Institute Consortium Collection. Surprisingly, in vitro, DISC1 aggregates were cell-invasive, i.e., purified aggresomes or recombinant DISC1 fragments where internalized at an efficiency comparable to that of α-synuclein. Intracellular DISC1 aggresomes acquired gain-of-function properties in recruiting otherwise soluble proteins such as the candidate schizophrenia protein dysbindin. Disease-associated DISC1 polymorphism S704C led to a higher oligomerization tendency of DISC1. These findings justify classification of DISC1-dependent brain disorders as protein conformational disorders which we have tentatively termed DISC1opathies. The notion of disturbed proteostasis and protein aggregation as a mechanism of mental diseases is thus emerging. The yet unidentified form of neuronal impairment in CMD is more subtle than in the classical neurodegenerative diseases without leading to massive cell death and as such present a different kind of neuronal dysfunctionality, eventually confined to highly selective CNS subpopulations.     

Topographic assessment of retinal pigment epithelium detachment in central serous chorioretinopathy by three-dimensional optical coherence tomography single-layer retinal pigment epithelium map

Purpose

This study aims to compare the topographic distribution of retinal pigment epithelium detachment (PED) in central serous chorioretinopathy (CSC) on spectral domain optical coherence tomography (SD-OCT) single-layer retinal pigment epithelium (SL-RPE) map and fluorescein angiography for the first time.

Methods

Twenty-seven eyes of CSC with PEDs were studied retrospectively. Topographic distribution of PEDs was documented on 50° fluorescein angiography and SD-OCT SL-RPE map on macular cube 512?×?128.

Results

Quantity of PEDs ranged from 1 to 5 on SD-OCT SL-RPE map macular cube 512?×?128 and corresponding macular cube area on 50° fluorescein angiography. Topographic distribution of PEDs on SL-RPE map matched with PEDs on fluorescein angiography in the corresponding macular cube area, in all the cases (interobserver correlation?=?0.9).

Conclusion

SD-OCT SL-RPE map is a noninvasive, three-dimensional advanced tool for documentation of topographic assessment of PEDs and obviates the need of fluorescein angiography for monitoring CSC.     

Proteomic analysis of lysine acetylation sites in rat tissues reveals organ specificity and subcellular patterns

Lysine acetylation is a major posttranslational modification involved in a broad array of physiological functions. Here, we provide an organ-wide map of lysine acetylation sites from 16 rat tissues analyzed by high-resolution tandem mass spectrometry. We quantify 15,474 modification sites on 4,541 proteins and provide the data set as a web-based database. We demonstrate that lysine acetylation displays site-specific sequence motifs that diverge between cellular compartments, with a significant fraction of nuclear sites conforming to the consensus motifs G-AcK and AcK-P. Our data set reveals that the subcellular acetylation distribution is tissue-type dependent and that acetylation targets tissue-specific pathways involved in fundamental physiological processes. We compare lysine acetylation patterns for rat as well as human skeletal muscle biopsies and demonstrate its general involvement in muscle contraction. Furthermore, we illustrate that acetylation of fructose-bisphosphate aldolase and glycerol-3-phosphate dehydrogenase serves as a cellular mechanism to switch off enzymatic activity.     

Mutations of the EPHB6 Receptor Tyrosine Kinase Induce a Pro-Metastatic Phenotype in Non-Small Cell Lung Cancer

Alterations of Eph receptor tyrosine kinases are frequent events in human cancers. Genetic variations of EPHB6 have been described but the functional outcome of these alterations is unknown. The current study was conducted to screen for the occurrence and to identify functional consequences of EPHB6 mutations in non-small cell lung cancer. Here, we sequenced the entire coding region of EPHB6 in 80 non-small cell lung cancer patients and 3 tumor cell lines. Three potentially relevant mutations were identified in primary patient samples of NSCLC patients (3.8%). Two point mutations led to instable proteins. An in frame deletion mutation (del915-917) showed enhanced migration and accelerated wound healing in vitro. Furthermore, the del915-917 mutation increased the metastatic capability of NSCLC cells in an in vivo mouse model. Our results suggest that EPHB6 mutations promote metastasis in a subset of patients with non-small cell lung cancer.     

Long-lasting hippocampal synaptic protein loss in a mouse model of posttraumatic stress disorder

Despite intensive research efforts, the molecular pathogenesis of posttraumatic stress disorder (PTSD) and especially of the hippocampal volume loss found in the majority of patients suffering from this anxiety disease still remains elusive. We demonstrated before that trauma-induced hippocampal shrinkage can also be observed in mice exhibiting a PTSD-like syndrome. Aiming to decipher the molecular correlates of these trans-species posttraumatic hippocampal alterations, we compared the expression levels of a set of neurostructural marker proteins between traumatized and control mice at different time points after their subjection to either an electric footshock or mock treatment which was followed by stressful re-exposure in several experimental groups. To our knowledge, this is the first systematic in vivo study analyzing the long-term neuromolecular sequelae of acute traumatic stress combined with re-exposure. We show here that a PTSD-like syndrome in mice is accompanied by a long-lasting reduction of hippocampal synaptic proteins which interestingly correlates with the strength of the generalized and conditioned fear response but not with the intensity of hyperarousal symptoms. Furthermore, we demonstrate that treatment with the serotonin reuptake inhibitor (SSRI) fluoxetine is able to counteract both the PTSD-like syndrome and the posttraumatic synaptic protein loss. Taken together, this study demonstrates for the first time that a loss of hippocampal synaptic proteins is associated with a PTSD-like syndrome in mice. Further studies will have to reveal whether these findings are transferable to PTSD patients.     

Led into Temptation? Rewarding Brand Logos Bias the Neural Encoding of Incidental Economic Decisions

Human decision-making is driven by subjective values assigned to alternative choice options. These valuations are based on reward cues. It is unknown, however, whether complex reward cues, such as brand logos, may bias the neural encoding of subjective value in unrelated decisions. In this functional magnetic resonance imaging (fMRI) study, we subliminally presented brand logos preceding intertemporal choices. We demonstrated that priming biased participants' preferences towards more immediate rewards in the subsequent temporal discounting task. This was associated with modulations of the neural encoding of subjective values of choice options in a network of brain regions, including but not restricted to medial prefrontal cortex. Our findings demonstrate the general susceptibility of the human decision making system to apparently incidental contextual information. We conclude that the brain incorporates seemingly unrelated value information that modifies decision making outside the decision-maker's awareness.     

Species history masks the effects of human-induced range loss--unexpected genetic diversity in the endangered giant mayfly Palingenia longicauda

Freshwater biodiversity has declined dramatically in Europe in recent decades. Because of massive habitat pollution and morphological degradation of water bodies, many once widespread species persist in small fractions of their original range. These range contractions are generally believed to be accompanied by loss of intraspecific genetic diversity, due to the reduction of effective population sizes and the extinction of regional genetic lineages. We aimed to assess the loss of genetic diversity and its significance for future potential reintroduction of the long-tailed mayfly Palingenia longicauda (Olivier), which experienced approximately 98% range loss during the past century. Analysis of 936 bp of mitochondrial DNA of 245 extant specimens across the current range revealed a surprisingly large number of haplotypes (87), and a high level of haplotype diversity (Hd = 0.875). In contrast, historic specimens (6) from the lost range (Rhine catchment) were not differentiated from the extant Rába population (F(ST) = 0.02, p = 0.61), despite considerable geographic distance separating the two rivers. These observations can be explained by an overlap of the current with the historic (Pleistocene) refugia of the species. Most likely, the massive recent range loss mainly affected the range which was occupied by rapid post-glacial dispersal. We conclude that massive range losses do not necessarily coincide with genetic impoverishment and that a species' history must be considered when estimating loss of genetic diversity. The assessment of spatial genetic structures and prior phylogeographic information seems essential to conserve once widespread species.     

Your unconscious knows your name

One''s own name constitutes a unique part of conscious awareness – but does this also hold true for unconscious processing? The present study shows that the own name has the power to bias a person''s actions unconsciously even in conditions that render any other name ineffective. Participants judged whether a letter string on the screen was a name or a non-word while this target stimulus was preceded by a masked prime stimulus. Crucially, the participant''s own name was among these prime stimuli and facilitated reactions to following name targets whereas the name of another, yoked participant did not. Signal detection results confirmed that participants were not aware of any of the prime stimuli, including their own name. These results extend traditional findings on “breakthrough” phenomena of personally relevant stimuli to the domain of unconscious processing. Thus, the brain seems to possess adroit mechanisms to identify and process such stimuli even in the absence of conscious awareness.