Cdh1-APC/C, cyclin B-Cdc2, and Alzheimer's disease pathology

The anaphase-promoting complex/cyclosome (APC/C) is a key E3 ubiquitin ligase complex that functions in regulating cell cycle transitions in proliferating cells and has, as revealed recently, novel roles in postmitotic neurons. Regulated by its activator Cdh1 (or Hct1), whose level is high in postmitotic neurons, APC/C seems to have multiple functions at different cellular locations, modulating diverse processes such as synaptic development and axonal growth. These processes do not, however, appear to be directly connected to cell cycle regulation. It is now shown that Cdh1-APC/C activity may also have a basic role in suppressing cyclin B levels, thus preventing terminally differentiated neurons from aberrantly re-entering the cell cycle. The result of an aberrant cyclin B-induced S-phase entry, at least for some of these neurons, would be death via apoptosis. Cdh1 thus play an active role in maintaining the terminally differentiated, non-cycling state of postmitotic neurons--a function that could become impaired in Alzheimer's and other neurodegenerative diseases.     

Saccharomyces Genome Database (SGD) provides biochemical and structural information for budding yeast proteins

The Saccharomyces Genome Database (SGD: http://genome-www.stanford.edu/Saccharomyces/) has recently developed new resources to provide more complete information about proteins from the budding yeast Saccharomyces cerevisiae. The PDB Homologs page provides structural information from the Protein Data Bank (PDB) about yeast proteins and/or their homologs. SGD has also created a resource that utilizes the eMOTIF database for motif information about a given protein. A third new resource is the Protein Information page, which contains protein physical and chemical properties, such as molecular weight and hydropathicity scores, predicted from the translated ORF sequence.     

Glucocerebrosidase Deficiency in Drosophila Results in α-Synuclein-Independent Protein Aggregation and Neurodegeneration

Mutations in the glucosidase, beta, acid (GBA1) gene cause Gaucher’s disease, and are the most common genetic risk factor for Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) excluding variants of low penetrance. Because α-synuclein-containing neuronal aggregates are a defining feature of PD and DLB, it is widely believed that mutations in GBA1 act by enhancing α-synuclein toxicity. To explore this hypothesis, we deleted the Drosophila GBA1 homolog, dGBA1b, and compared the phenotypes of dGBA1b mutants in the presence and absence of α-synuclein expression. Homozygous dGBA1b mutants exhibit shortened lifespan, locomotor and memory deficits, neurodegeneration, and dramatically increased accumulation of ubiquitinated protein aggregates that are normally degraded through an autophagic mechanism. Ectopic expression of human α-synuclein in dGBA1b mutants resulted in a mild enhancement of dopaminergic neuron loss and increased α-synuclein aggregation relative to controls. However, α-synuclein expression did not substantially enhance other dGBA1b mutant phenotypes. Our findings indicate that dGBA1b plays an important role in the metabolism of protein aggregates, but that the deleterious consequences of mutations in dGBA1b are largely independent of α-synuclein. Future work with dGBA1b mutants should reveal the mechanism by which mutations in dGBA1b lead to accumulation of protein aggregates, and the potential influence of this protein aggregation on neuronal integrity.     

Down-Regulation of Desmosomes in Cultured Cells: The Roles of PKC,Microtubules and Lysosomal/Proteasomal Degradation

Desmosomes are intercellular adhesive junctions of major importance for tissue integrity. To allow cell motility and migration they are down-regulated in epidermal wound healing. Electron microscopy indicates that whole desmosomes are internalised by cells in tissues, but the mechanism of down-regulation is unclear. In this paper we provide an overview of the internalisation of half-desmosomes by cultured cells induced by calcium chelation. Our results show that: (i) half desmosome internalisation is dependent on conventional PKC isoforms; (ii) microtubules transport internalised half desmosomes to the region of the centrosome by a kinesin-dependent mechanism; (iii) desmosomal proteins remain colocalised after internalisation and are not recycled to the cell surface; (iv) internalised desmosomes are degraded by the combined action of lysosomes and proteasomes. We also confirm that half desmosome internalisation is dependent upon the actin cytoskeleton. These results suggest that half desmosomes are not disassembled and recycled during or after internalisation but instead are transported to the centrosomal region where they are degraded. These findings may have significance for the down-regulation of desmosomes in wounds.     

Polyphyly of Caddoidea,reinstatement of the family Acropsopilionidae in Dyspnoi,and a revised classification system of Palpatores (Arachnida,Opiliones)

Among the least studied harvestmen are the members of the family Caddidae sensu Shear, 1975 , a group of Opiliones with massive eyes and the putative sister group of the remaining Eupnoi. Caddids were originally described as two families, Caddidae and Acropsopilionidae, but these are currently treated as subfamilies of Caddidae. These minute arachnids are rarely collected and present some interesting biogeographical patterns, including a disjunct distribution between East Asia and eastern North America, and some of the few cases of trans‐Pacific genera in southern hemisphere Opiliones. We therefore obtained samples from most of the landmasses inhabited by Caddidae and undertook a phylogenetic study using nuclear and mitochondrial genes for as many samples as possible. Our results, based on a broad taxonomic sampling, surprisingly showed polyphyly of Caddidae, with the genus Caddo forming the sister group of the remaining Eupnoi, whereas the southern hemisphere genera, many of which were originally placed in Acropsopilionidae, within Dyspnoi, formed the sister clade of the remaining Dyspnoi. In addition, the more recently described genus Hesperopilio, from Western Australia and Chile, was unrelated to either Caddidae or Acropsopilionidae, despite having the supposedly diagnostic large ocularium, and instead appeared deeply nested within the Eupnoi superfamily Phalangioidea. Our results are robust to analytical treatment and to homology scheme (dynamic vs. static notions of homology), resulting in a new phylogenetic proposal for Eupnoi and Dyspnoi. Ancestral state reconstruction suggests that the ancestral Palpatores was probably a tiny harvestman with an enlarged ocularium and glandular palpal setae in its enlarged and armed palps. We take the following taxonomic actions: Acropsopilionidae is removed from synonymy under Caddidae and its family status and membership in Dyspnoi are restored. Hesperopilio Shear, 1996 is removed from Caddoidea/Caddidae and transferred to Phalangioidea, but it is not assigned to any family.     

Neurodevelopmental toxicity assessment of flame retardants using a human DNT in vitro testing battery

Due to their neurodevelopmental toxicity, flame retardants (FRs) like polybrominated diphenyl ethers are banned from the market and replaced by alternative FRs, like organophosphorus FRs, that have mostly unknown toxicological profiles. To study their neurodevelopmental toxicity, we evaluated the hazard of several FRs including phased-out polybrominated FRs and organophosphorus FRs: 2,2′,4,4′-tetrabromodiphenylether (BDE-47), 2,2′,4,4′,5-pentabromodiphenylether (BDE-99), tetrabromobisphenol A, triphenyl phosphate, tris(2-butoxyethyl) phosphate and its metabolite bis-(2-butoxyethyl) phosphate, isodecyl diphenyl phosphate, triphenyl isopropylated phosphate, tricresyl phosphate, tris(1,3-dichloro-2-propyl) phosphate, tert-butylphenyl diphenyl phosphate, 2-ethylhexyl diphenyl phosphate, tris(1-chloroisopropyl) phosphate, and tris(2-chloroethyl) phosphate. Therefore, we used a human cell–based developmental neurotoxicity (DNT) in vitro battery covering a large variety of neurodevelopmental endpoints. Potency according to the respective most sensitive benchmark concentration (BMC) across the battery ranked from <1 μM (5 FRs), 1<10 μM (7 FRs) to the >10 μM range (3 FRs). Evaluation of the data with the ToxPi tool revealed a distinct ranking (a) than with the BMC and (b) compared to the ToxCast data, suggesting that DNT hazard of these FRs is not well predicted by ToxCast assays. Extrapolating the DNT in vitro battery BMCs to human FR exposure via breast milk suggests low risk for individual compounds. However, it raises a potential concern for real-life mixture exposure, especially when different compounds converge through diverse modes-of-action on common endpoints, like oligodendrocyte differentiation in this study. This case study using FRs suggests that human cell–based DNT in vitro battery is a promising approach for neurodevelopmental hazard assessment and compound prioritization in risk assessment.

Graphical abstract

     

Biparental contributions of the H2A.B histone variant control embryonic development in mice

Histone variants expand chromatin functions in eukaryote genomes. H2A.B genes are testis-expressed short histone H2A variants that arose in placental mammals. Their biological functions remain largely unknown. To investigate their function, we generated a knockout (KO) model that disrupts all 3 H2A.B genes in mice. We show that H2A.B KO males have globally altered chromatin structure in postmeiotic germ cells. Yet, they do not show impaired spermatogenesis or testis function. Instead, we find that H2A.B plays a crucial role postfertilization. Crosses between H2A.B KO males and females yield embryos with lower viability and reduced size. Using a series of genetic crosses that separate parental and zygotic contributions, we show that the H2A.B status of both the father and mother, but not of the zygote, affects embryonic viability and growth during gestation. We conclude that H2A.B is a novel parental-effect gene, establishing a role for short H2A histone variants in mammalian development. We posit that parental antagonism over embryonic growth drove the origin and ongoing diversification of short histone H2A variants in placental mammals.

The unusual short histone variant H2A.B is a novel parental-effect gene that plays an important role in early mammalian development. Parental antagonism over embryonic growth resource allocation may have driven the origin and ongoing diversification of short histone H2A variants in placental mammals.     

Development, set-up and first results for a one-channel near-infrared spectroscopy system.

Abstract Near-infrared spectroscopy (NIRS) is a non-invasive optical technique that can be used to assess functional activity in the human brain. This work describes the set-up of a one-channel NIRS system designed for use as an optical brain-computer interface (BCI) and reports on first measurements of deoxyhemoglobin (Hb) and oxyhemoglobin (HbO(2)) changes during mental arithmetic tasks. We found relatively stable and reproducible hemodynamic responses in a group of 13 healthy subjects. Unexpected observations of a decrease in HbO(2) and increase in Hb concentrations measured over the prefrontal cortex were in contrast to the typical hemodynamic responses (increase in HbO(2), decrease in Hb) during cortical activation previously reported.