Interaction of tau protein with model lipid membranes induces tau structural compaction and membrane disruption

The misfolding and aggregation of the intrinsically disordered, microtubule-associated tau protein into neurofibrillary tangles is implicated in the pathogenesis of Alzheimer's disease. However, the mechanisms of tau aggregation and toxicity remain unknown. Recent work has shown that anionic lipid membranes can induce tau aggregation and that membrane permeabilization may serve as a pathway by which protein aggregates exert toxicity, suggesting that the plasma membrane may play dual roles in tau pathology. This prompted our investigation to assess tau's propensity to interact with membranes and to elucidate the mutually disruptive structural perturbations the interactions induce in both tau and the membrane. We show that although highly charged and soluble, the full-length tau (hTau40) is also highly surface active, selectively inserts into anionic DMPG lipid monolayers and induces membrane morphological changes. To resolve molecular-scale structural details of hTau40 associated with lipid membranes, X-ray and neutron scattering techniques are utilized. X-ray reflectivity indicates hTau40s presence underneath a DMPG monolayer and penetration into the lipid headgroups and tailgroups, whereas grazing incidence X-ray diffraction shows that hTau40 insertion disrupts lipid packing. Moreover, both air/water and DMPG lipid membrane interfaces induce the disordered hTau40 to partially adopt a more compact conformation with density similar to that of a folded protein. Neutron reflectivity shows that tau completely disrupts supported DMPG bilayers while leaving the neutral DPPC bilayer intact. Our results show that hTau40s strong interaction with anionic lipids induces tau structural compaction and membrane disruption, suggesting possible membrane-based mechanisms of tau aggregation and toxicity in neurodegenerative diseases.     

Multisensory Control of Multimodal Behavior: Do the Legs Know What the Tongue Is Doing?

Understanding of adaptive behavior requires the precisely controlled presentation of multisensory stimuli combined with simultaneous measurement of multiple behavioral modalities. Hence, we developed a virtual reality apparatus that allows for simultaneous measurement of reward checking, a commonly used measure in associative learning paradigms, and navigational behavior, along with precisely controlled presentation of visual, auditory and reward stimuli. Rats performed a virtual spatial navigation task analogous to the Morris maze where only distal visual or auditory cues provided spatial information. Spatial navigation and reward checking maps showed experience-dependent learning and were in register for distal visual cues. However, they showed a dissociation, whereby distal auditory cues failed to support spatial navigation but did support spatially localized reward checking. These findings indicate that rats can navigate in virtual space with only distal visual cues, without significant vestibular or other sensory inputs. Furthermore, they reveal the simultaneous dissociation between two reward-driven behaviors.     

Genetic structure,diversity, and hybridization in populations of the rare arctic relict <Emphasis Type="Italic">Euphrasia hudsoniana</Emphasis> (Orobanchaceae) and its invasive congener <Emphasis Type="Italic">Euphrasia stricta</Emphasis>

Arctic relict populations, which persist in disjunct locations far south of a species’ normal range, are at the frontline of climate change and may be especially susceptible to the negative impacts of climate warming. Further, these relict populations may face increasing contact with, or become outcompeted by, invasive species if the invasive taxa are spreading along with the warming climate. Relict populations are simultaneously of particular conservation importance due to their unique genetic make-up and potential for adaptations to warmer temperatures compared to populations at the core of the species range. In this study, we used genotyping-by-sequencing to study the population genetics of Euphrasia hudsoniana, a polyploid arctic disjunct of conservation concern, at the southern edge of its range along the northwestern shore of Lake Superior. In addition, we examined evidence for hybridization with its invasive congener, E. stricta. Overall, we found clear differentiation between the native and invasive species indicated by nearly all analyses. There was limited evidence for gene flow from the invasive into the native species, but patterns were consistent with more extensive gene flow in the opposite direction. Differentiation among native populations was low, yet two of the five populations fell into a separate, distinct group based on STRUCTURE analyses. Continued genetic monitoring of these populations will help elucidate whether hybridization with invasives is a burgeoning threat for this arctic relict.     

Genomic patterns of nucleotide diversity in divergent populations of U.S. weedy rice

Background  

Weedy rice (red rice), a conspecific weed of cultivated rice (Oryza sativa L.), is a significant problem throughout the world and an emerging threat in regions where it was previously absent. Despite belonging to the same species complex as domesticated rice and its wild relatives, the evolutionary origins of weedy rice remain unclear. We use genome-wide patterns of single nucleotide polymorphism (SNP) variation in a broad geographic sample of weedy, domesticated, and wild Oryza samples to infer the origin and demographic processes influencing U.S. weedy rice evolution.     

Origin(s) of the diploid hybrid species Helianthus deserticola (Asteraceae)

Homoploid hybrid speciation has traditionally been considered a rare event, dependent on the establishment of both a novel, balanced genotype and reproductive isolating barriers between the new species and its progenitors. However, more recent studies have shown that synthetic hybrids converge toward the chromosomal structure of natural hybrids after only a few generations, suggesting that this phenomenon may be more frequent than previously assumed. Here, the possibility that the diploid hybrid species Helianthus deserticola arose from more than one hybrid speciation event was investigated using patterns of variation from cpDNA, 18 nuclear microsatellite loci, and population interfertility. Helianthus deserticola contains cpDNA haplotypes characteristic of both parental species, is polyphyletic with one parental species based on nine microsatellite loci, and has a high degree of interfertility among populations. The data are consistent with either a single origin followed by introgression with the parental species or multiple origins. Analysis of microsatellite variation places the origin of H. deserticola between 170?000 and 63?000 years before present, making it unlikely that anthropogenic disturbances influenced its origin. Finally, the hybrid species generally has lower levels of genetic diversity but higher levels of differentiation among populations than either parental species.     

Reconstructing the origin of Helianthus deserticola: survival and selection on the desert floor

The diploid hybrid species Helianthus deserticola inhabits the desert floor, an extreme environment relative to its parental species Helianthus annuus and Helianthus petiolaris. Adaptation to the desert floor may have occurred via selection acting on transgressive, or extreme, traits in early hybrids between the parental species. We explored this possibility through a field experiment in the hybrid species' native habitat using H. deserticola, H. annuus, H. petiolaris, and two populations of early-generation (BC(2)) hybrids between the parental species, which served as proxies for the ancestral genotype of the ancient hybrid species. Character expression was evaluated for each genotypic class. Helianthus deserticola was negatively transgressive for stem diameter, leaf area, and flowering date, and the latter two traits are likely to be advantageous in a desert environment. The BC(2) hybrids contained a range of variation that overlapped these transgressive trait means, and an analysis of phenotypic selection revealed that some of the selective pressures on leaf size and flowering date, but not stem diameter, would move the BC(2) population toward the H. deserticola phenotype. Thus, H. deserticola may have originated from habitat-mediated directional selection acting on hybrids between H. annuus and H. petiolaris in a desert environment.     

Analysis of the amino acid sequence specificity determinants of the enterococcal cCF10 sex pheromone in interactions with the pheromone-sensing machinery

The level of expression of conjugation genes in Enterococcus faecalis strains carrying the pheromone-responsive transferable plasmid pCF10 is determined by the ratio in the culture medium of two types of signaling peptides, a pheromone (cCF10) and an inhibitor (iCF10). Recent data have demonstrated that both peptides target the cytoplasmic receptor protein PrgX. However, the relative importance of the interaction of these peptides with the pCF10 protein PrgZ (which enhances import of cCF10) versus PrgX is not fully understood, and there is relatively little information about specific amino acid sequence determinants affecting the functional interactions of cCF10 with these proteins in vivo. To address these issues, we used a pheromone-inducible reporter gene system where various combinations of PrgX and PrgZ could be expressed in an isogenic host background to examine the biological activities of cCF10, iCF10, and variants of cCF10 isolated in a genetic screen. The results suggest that most of the amino acid sequence determinants of cCF10 pheromone activity affect interactions between the peptide and PrgX, although some sequence variants that affected peptide/PrgZ interactions were also identified. The results provide functional data to complement ongoing structural studies of PrgX and increase our understanding of the functional interactions of cCF10 and iCF10 with the pheromone-sensing machinery of pCF10.     

Oral branched-chain amino acid supplements that reduce brain serotonin during exercise in rats also lower brain catecholamines

Exercise raises brain serotonin release and is postulated to cause fatigue in athletes; ingestion of branched-chain amino acids (BCAA), by competitively inhibiting tryptophan transport into brain, lowers brain tryptophan uptake and serotonin synthesis and release in rats, and reputedly in humans prevents exercise-induced increases in serotonin and fatigue. This latter effect in humans is disputed. But BCAA also competitively inhibit tyrosine uptake into brain, and thus catecholamine synthesis and release. Since increasing brain catecholamines enhances physical performance, BCAA ingestion could lower catecholamines, reduce performance and thus negate any serotonin-linked benefit. We therefore examined in rats whether BCAA would reduce both brain tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis. Sedentary and exercising rats received BCAA or vehicle orally; tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis rates were measured 1 h later in brain. BCAA reduced brain tryptophan and tyrosine concentrations, and serotonin and catecholamine synthesis. These reductions in tyrosine concentrations and catecholamine synthesis, but not tryptophan or serotonin synthesis, could be prevented by co-administering tyrosine with BCAA. Complete essential amino acid mixtures, used to maintain or build muscle mass, were also studied, and produced different effects on brain tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis. Since pharmacologically increasing brain catecholamine function improves physical performance, the finding that BCAA reduce catecholamine synthesis may explain why this treatment does not enhance physical performance in humans, despite reducing serotonin synthesis. If so, adding tyrosine to BCAA supplements might allow a positive action on performance to emerge.