<Emphasis Type="Italic">ABI3</Emphasis> and <Emphasis Type="Italic">PLCG2</Emphasis> missense variants as risk factors for neurodegenerative diseases in Caucasians and African Americans

Background

Rare coding variants ABI3_rs616338-T and PLCG2_rs72824905-G were identified as risk or protective factors, respectively, for Alzheimer’s disease (AD).

Methods

We tested the association of these variants with five neurodegenerative diseases in Caucasian case-control cohorts: 2742 AD, 231 progressive supranuclear palsy (PSP), 838 Parkinson’s disease (PD), 306 dementia with Lewy bodies (DLB) and 150 multiple system atrophy (MSA) vs. 3351 controls; and in an African-American AD case-control cohort (181 AD, 331 controls). 1479 AD and 1491 controls were non-overlapping with a prior report.

Results

Using Fisher’s exact test, there was significant association of both ABI3_rs616338-T (OR?=?1.41, p?=?0.044) and PLCG2_rs72824905-G (OR?=?0.56, p?=?0.008) with AD. These OR estimates were maintained in the non-overlapping replication AD-control analysis, albeit at reduced significance (ABI3_rs616338-T OR?=?1.44, p?=?0.12; PLCG2_rs72824905-G OR?=?0.66, p?=?0.19). None of the other cohorts showed significant associations that were concordant with those for AD, although the DLB cohort had suggestive findings (Fisher’s test: ABI3_rs616338-T OR?=?1.79, p?=?0.097; PLCG2_rs72824905-G OR?=?0.32, p?=?0.124). PLCG2_rs72824905-G showed suggestive association with pathologically-confirmed MSA (OR?=?2.39, p?=?0.050) and PSP (OR?=?1.97, p?=?0.061), although in the opposite direction of that for AD. We assessed RNA sequencing data from 238 temporal cortex (TCX) and 224 cerebellum (CER) samples from AD, PSP and control patients and identified co-expression networks, enriched in microglial genes and immune response GO terms, and which harbor PLCG2 and/or ABI3. These networks had higher expression in AD, but not in PSP TCX, compared to controls. This expression association did not survive adjustment for brain cell type population changes.

Conclusions

We validated the associations previously reported with ABI3_rs616338-T and PLCG2_rs72824905-G in a Caucasian AD case-control cohort, and observed a similar direction of effect in DLB. Conversely, PLCG2_rs72824905-G showed suggestive associations with PSP and MSA in the opposite direction. We identified microglial gene-enriched co-expression networks with significantly higher levels in AD TCX, but not in PSP, a primary tauopathy. This co-expression network association appears to be driven by microglial cell population changes in a brain region affected by AD pathology. Although these findings require replication in larger cohorts, they suggest distinct effects of the microglial genes, ABI3 and PLCG2 in neurodegenerative diseases that harbor significant vs. low/no amyloid ß pathology.

     

Epoxyqueuosine Reductase Structure Suggests a Mechanism for Cobalamin-dependent tRNA Modification

Queuosine (Q) is a hypermodified RNA base that replaces guanine in the wobble positions of 5′-GUN-3′ tRNA molecules. Q is exclusively made by bacteria, and the corresponding queuine base is a micronutrient salvaged by eukaryotic species. The final step in Q biosynthesis is the reduction of the epoxide precursor, epoxyqueuosine, to yield the Q cyclopentene ring. The epoxyqueuosine reductase responsible, QueG, shares distant homology with the cobalamin-dependent reductive dehalogenase (RdhA), however the role played by cobalamin in QueG catalysis has remained elusive. We report the solution and structural characterization of Streptococcus thermophilus QueG, revealing the enzyme harbors a redox chain consisting of two [4Fe-4S] clusters and a cob(II)alamin in the base-off form, similar to RdhAs. In contrast to the shared redox chain architecture, the QueG active site shares little homology with RdhA, with the notable exception of a conserved Tyr that is proposed to function as a proton donor during reductive dehalogenation. Docking of an epoxyqueuosine substrate suggests the QueG active site places the substrate cyclopentane moiety in close proximity of the cobalt. Both the Tyr and a conserved Asp are implicated as proton donors to the epoxide leaving group. This suggests that, in contrast to the unusual carbon-halogen bond chemistry catalyzed by RdhAs, QueG acts via Co-C bond formation. Our study establishes the common features of Class III cobalamin-dependent enzymes, and reveals an unexpected diversity in the reductive chemistry catalyzed by these enzymes.     

PHOTOINHIBITION AND PHOTOACCLIMATION OF TURF ALGAL COMMUNITIES ON A TEMPERATE REEF,AFTER IN SITU TRANSPLANTATION EXPERIMENTS1

The photophysiology of turf algal communities was studied in situ on a temperate reef off the coast of South Australia. Algal communities were grown on artificial substrate at depths of 2, 4, and 10 m. To investigate the response of the algal communities to changing light environments in both the short and long term, reciprocal transplantation experiments were conducted among these depths on a seasonal basis. The extent of photoinhibition was assessed every 3 h for the first 2 days following transplantation and then on a daily basis for 16 days after transplantation. Photosynthetic acclimation was assessed using photosynthesis–light curves obtained from transplanted and non‐transplanted turfs after the acclimation period. Transplanted turfs responded very quickly to the light shift. Algae acclimated to low light (10 m depth) were highly susceptible to photoinhibition and photodamage, having greater decreases in maximum and effective quantum yields than turfs from shallower depths. Yield recovery and acclimation usually occurred very rapidly in algae from all depths (3–5 days), but were faster in spring and summer compared with winter. Changes in photosynthetic capacity (across seasons, depths, and after transplantation to a different depth) were accompanied by changes in respiration, so that the ratio of net to gross photosynthetic capacity (P_mnet : P_mgross) remained high and constant over the whole range of light levels. We discuss the possible acclimation strategies of turfs, taking into account the balance between photoacclimation, production, and growth strategy.     

Effect of periodate oxidation on the polysaccharide content and microaggregate stability of rhizosphere and non-rhizosphere soils

Summary The relationship between the stability of soil microaggregates in water and the polysaccharide content was examined in rhizosphere and non-rhizosphere samples from a pot experiment using three soils that had grown peas, barley or grasses. The polysaccharide was oxidised and removed using 168h treatment with 0.02M periodate followed by 6h with 0.1M tetraborate. The decrease in polysaccharide content, measured as change in residual reducing sugars, was compared with the stability of soil microaggregates (ca 45m) in water, determined by a turbidimetric method.Total C, N and polysaccharide contents of rhizosphere soils were greater than those for the bulk soil, but the water stability of aggregates was not increased compared to unplanted controls. Periodate oxidation removed a large proportion (59–95%) of the polysaccharide and increased aggregated disruption, but there was no clear relationship between the two measurements. In rhizosphere soil, polysaccharides appreared to make less contribution to aggregate stability than polysaccharide in the bulk soil. The relatively small effect of rhizosphere polysaccharides is probably related to their presence as comparatively massive plant remains and debris; this contrasts with the decomposed and transformed material in the bulk soil.     

A CLADISTIC ANALYSIS OF THE EVOLUTION AND BIOGEOGRAPHY OF DURVILLAEA (PHAEOPHYTA)1

The genus Durvillaea currently has four recognized species found along many exposed, rocky coastlines of the temperate to sub-Antarctic regions in the Southern Hemisphere. We propose that the current species distributions are related primarily to vicariance events and subsequent speciation associated with the breakup of Gondwana between 40 and 100 Ma. From an ancestral species, a stipitate species developed in the Tasman basin, with separation and speciation resulting in the D. potatorum/ D. willana complex in southeastern Australia and New Zealand. A second line of evolution led to D. chathamensis and D. antarctica characterized by a honeycombed medulla. The extensive distribution of D. antarctica throughout the Southern Hemisphere is related to both vicariance and dispersal events. The status of D. chathamensis as a species distinct from D. antarctica is questioned. The affinities of an as yet undescribed taxon from the Antipodes Islands are thought to be with the D. potatorum complex but require further study before they can be defined more precisely .     

Patterns in the distribution of sponge populations across the central Great Barrier Reef

Coral reef sponge populations were surveyed at two spatial scales: different depths and different reef locations across the continental shelf of the central Great Barrier Reef. The surveys were conducted on the forereef slopes of 12 reefs from land-influenced, inner-shelf reefs to those in the oligotrophic waters of the Coral Sea. Few sponges occur in shallow waters and the largest populations are found between 10 and 30 m depth. Sponges are apparently excluded from shallow waters because of excessive turbulence and possibly by high levels of damaging light. Sponge biomass is highest on the innershelf reefs and decreases away from the coast, whereas abundance is generally higher on middle-shelf reefs. There are considerable overlaps in the species composition on middle-, outer-shelf and Coral Sea reefs, but those on inner-shelf reefs are significantly different. The nature and size of sponge populations reflect environmental conditions across the continental shelf. The larger inner-shelf populations probably reflect higher levels of organic and inorganic nutrients and reduced amounts of physical turbulence, whereas sponges on reefs further from shore may be able to resist greater turbulence but appear more sensitive to the effects of fine sediments. These latter populations are smaller, reflecting the reduced availability of organic matter, however, many of these sponges rely on cyanobacterial symbionts to augment nutrition in these clearer, more oligotrophic waters.Contribution no. 487 from the Australian Institute of Marine Science     

Structure-activity relationships in beta-defensin peptides

The beta-defensins comprise a large family of small cationic antimicrobial peptides widely distributed in plants, mammals and insects. These cysteine rich peptides display multifunctional properties with implications as potential therapeutic agents. Recent research has highlighted their role in both the innate and adaptive immune systems as well as being novel melanocortin ligands. Studies investigating structure and function provide an insight into the molecular basis of their immunological properties.     

The complexity of selection at the major primate β-defensin locus

Background  

We have examined the evolution of the genes at the major human β-defensin locus and the orthologous loci in a range of other primates and mouse. For the first time these data allow us to examine selective episodes in the more recent evolutionary history of this locus as well as the ancient past. We have used a combination of maximum likelihood based tests and a maximum parsimony based sliding window approach to give a detailed view of the varying modes of selection operating at this locus.     

Arabidopsis AtCUL3a and AtCUL3b form complexes with members of the BTB/POZ-MATH protein family

The ubiquitin proteasome pathway in plants has been shown to be important for many developmental processes. The E3 ubiquitin-protein ligases facilitate transfer of the ubiquitin moiety to substrate proteins. Many E3 ligases contain cullin proteins as core subunits. Here, we show that Arabidopsis (Arabidopsis thaliana) AtCUL3 proteins interact in yeast two-hybrid and in vitro pull-down assays with proteins containing a BTB/POZ (broad complex, tramtrack, bric-a-brac/pox virus and zinc finger) motif. By changing specific amino acid residues within the proteins, critical parts of the cullin and BTB/POZ proteins are defined that are required for these kinds of interactions. In addition, we show that AtCUL3 proteins assemble with the RING-finger protein AtRBX1 and are targets for the RUB-conjugation pathway. The analysis of AtCUL3a and AtCUL3b expression as well as several BTB/POZ-MATH genes indicates that these genes are expressed in all parts of the plant. The results presented here provide strong evidence that AtCUL3a and AtCUL3b can assemble in Arabidopsis with BTB/POZ-MATH and AtRBX1 proteins to form functional E3 ligases.