Ube3a,the E3 ubiquitin ligase causing Angelman syndrome and linked to autism,regulates protein homeostasis through the proteasomal shuttle Rpn10

Ubiquitination, the covalent attachment of ubiquitin to a target protein, regulates most cellular processes and is involved in several neurological disorders. In particular, Angelman syndrome and one of the most common genomic forms of autism, dup15q, are caused respectively by lack of or excess of UBE3A, a ubiquitin E3 ligase. Its Drosophila orthologue, Ube3a, is also active during brain development. We have now devised a protocol to screen for substrates of this particular ubiquitin ligase. In a neuronal cell system, we find direct ubiquitination by Ube3a of three proteasome-related proteins Rpn10, Uch-L5, and CG8209, as well as of the ribosomal protein Rps10b. Only one of these, Rpn10, is targeted for degradation upon ubiquitination by Ube3a, indicating that degradation might not be the only effect of Ube3a on its substrates. Furthermore, we report the genetic interaction in vivo between Ube3a and the C-terminal part of Rpn10. Overexpression of these proteins leads to an enhanced accumulation of ubiquitinated proteins, further supporting the biochemical evidence of interaction obtained in neuronal cells.     

Non-Fermi-liquid behaviour in La4Ru6O19

Understanding the complexities of electronic and magnetic ground states in solids is one of the main goals of solid-state physics. Transition-metal oxides have proved to be particularly fruitful in this regard, especially for those materials with the perovskite structure, where the special characteristics of transition-metal-oxygen orbital hybridization determine their properties. Ruthenates have recently emerged as an important family of perovskites because of the unexpected evolution from high-temperature ferromagnetism in SrRuO3 to low-temperature superconductivity in Sr2RuO4 (refs 1, 2). Here we show that a ruthenate in a different structural family, La4Ru6O19, displays a number of highly unusual properties, most notably non-Fermi-liquid behaviour. The properties of La4Ru6O19 have no analogy among the thousands of previously characterized transition-metal oxides. Instead, they resemble those of CeCu6-xAux-a widely studied f-electron-based heavy fermion intermetallic compound that is often considered as providing the best example of non-Fermi-liquid behaviour. In the ruthenate, non-Fermi-liquid behaviour appears to arise from just the right balance between the interactions of localized electronic states derived from Ru-Ru bonding and delocalized states derived from Ru-O hybridization.     

Superconductivity in the non-oxide perovskite MgCNi3

The interplay of magnetic interactions, the dimensionality of the crystal structure and electronic correlations in producing superconductivity is one of the dominant themes in the study of the electronic properties of complex materials. Although magnetic interactions and two-dimensional structures were long thought to be detrimental to the formation of a superconducting state, they are actually common features of both the high transition-temperature (Tc) copper oxides and low-Tc material Sr2RuO4, where they appear to be essential contributors to the exotic electronic states of these materials. Here we report that the perovskite-structured compound MgCNi3 is superconducting with a critical temperature of 8 K. This material is the three-dimensional analogue of the LnNi2B2C family of superconductors, which have critical temperatures up to 16 K (ref. 2). The itinerant electrons in both families of materials arise from the partial filling of the nickel d-states, which generally leads to ferromagnetism as is the case in metallic Ni. The high relative proportion of Ni in MgCNi3 suggests that magnetic interactions are important, and the lower Tc of this three-dimensional compound-when compared to the LnNi2B2C family-contrasts with conventional ideas regarding the origins of superconductivity.     

Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome

Marfan syndrome is an autosomal dominant disorder of connective tissue caused by mutations in fibrillin-1 (encoded by FBN1 in humans and Fbn1 in mice), a matrix component of extracellular microfibrils. A distinct subgroup of individuals with Marfan syndrome have distal airspace enlargement, historically described as emphysema, which frequently results in spontaneous lung rupture (pneumothorax; refs. 1-3). To investigate the pathogenesis of genetically imposed emphysema, we analyzed the lung phenotype of mice deficient in fibrillin-1, an accepted model of Marfan syndrome. Lung abnormalities are evident in the immediate postnatal period and manifest as a developmental impairment of distal alveolar septation. Aged mice deficient in fibrillin-1 develop destructive emphysema consistent with the view that early developmental perturbations can predispose to late-onset, seemingly acquired phenotypes. We show that mice deficient in fibrillin-1 have marked dysregulation of transforming growth factor-beta (TGF-beta) activation and signaling, resulting in apoptosis in the developing lung. Perinatal antagonism of TGF-beta attenuates apoptosis and rescues alveolar septation in vivo. These data indicate that matrix sequestration of cytokines is crucial to their regulated activation and signaling and that perturbation of this function can contribute to the pathogenesis of disease.     

Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes.

Marfan syndrome (MFS), one of the most common genetic disorders of connective tissue, is characterized by skeletal, cardiovascular and ocular abnormalities. The incidence of the disease is about 1 in 20,000, with life expectancy severely reduced because of cardiovascular complications. As the underlying defect is unknown, MFS diagnosis is based solely on clinical criteria. Certain phenotypic features of MFS are also shared by other conditions, which may be genetically distinct entities although part of a clinical continuum. Immunohistochemical studies have implicated fibrillin, a major component of elastin-associated microfibrils, in MFS aetiology. Genetic linkage analysis with random probes has independently localized the MFS locus to chromosome 15. Here we report that these two experimental approaches converge with the cloning and mapping of the fibrillin gene to chromosome 15q15-21, and with the establishment of linkage to MFS. We also isolated a second fibrillin gene and mapped it to chromosome 5q23-31. We linked this novel gene to a condition, congenital contractural arachnodactyly, that shares some of the features of MFS. Thus, the cosegregation of two related genes with two related syndromes implies that fibrillin mutations are likely to be responsible for different MFS phenotypes.     

Recommendations of the 2006 Human Variome Project meeting

Lists of variations in genomic DNA and their effects have been kept for some time and have been used in diagnostics and research. Although these lists have been carefully gathered and curated, there has been little standardization and coordination, complicating their use. Given the myriad possible variations in the estimated 24,000 genes in the human genome, it would be useful to have standard criteria for databases of variation. Incomplete collection and ascertainment of variants demonstrates a need for a universally accessible system. These and other problems led to the World Heath Organization-cosponsored meeting on June 20-23, 2006 in Melbourne, Australia, which launched the Human Variome Project. This meeting addressed all areas of human genetics relevant to collection of information on variation and its effects. Members of each of eight sessions (the clinic and phenotype, the diagnostic laboratory, the research laboratory, curation and collection, informatics, relevance to the emerging world, integration and federation and funding and sustainability) developed a number of recommendations that were then organized into a total of 96 recommendations to act as a foundation for future work worldwide. Here we summarize the background of the project, the meeting and its recommendations.     

CDK5 downregulation enhances synaptic plasticity

CDK5 is a serine/threonine kinase that is involved in the normal function of the adult brain and plays a role in neurotransmission and synaptic plasticity. However, its over-regulation has been associated with Tau hyperphosphorylation and cognitive deficits. Our previous studies have demonstrated that CDK5 targeting using shRNA-miR provides neuroprotection and prevents cognitive deficits. Dendritic spine morphogenesis and forms of long-term synaptic plasticity—such as long-term potentiation (LTP)—have been proposed as essential processes of neuroplasticity. However, whether CDK5 participates in these processes remains controversial and depends on the experimental model. Using wild-type mice that received injections of CDK5 shRNA-miR in CA1 showed an increased LTP and recovered the PPF in deficient LTP of APPswe/PS1Δ9 transgenic mice. On mature hippocampal neurons CDK5, shRNA-miR for 12 days induced increased dendritic protrusion morphogenesis, which was dependent on Rac activity. In addition, silencing of CDK5 increased BDNF expression, temporarily increased phosphorylation of CaMKII, ERK, and CREB; and facilitated calcium signaling in neurites. Together, our data suggest that CDK5 downregulation induces synaptic plasticity in mature neurons involving Ca²⁺ signaling and BDNF/CREB activation.     

Regional variations and particle binding of free amino acids in the rat brain: effects of amphetamine and methaqualone]

Amphetamine and methaqualone affected aspartate level in various regions of Rat brain. Increased aspartate level in cerebral cortex of methaqualone treated Rats was produced in the aspartate fraction whose binding to subcellular particules was Na+ dependant. This work suggest that aspartate level was altered only in brain fraction implicated in the pharmacological effects of the drugs.     

The SNRPN promoter is not required for genomic imprinting of the Prader-Willi/Angelman domain in mice.

In mice and humans, the locus encoding the gene for small nuclear ribonucleoprotein N (SNRPN/Snrpn), as well as other loci in the region are subject to genomic imprinting. The SNRPN promoter is embedded in a maternally methylated CpG island, is expressed only from the paternal chromosome and lies within an imprinting center that is required for switching to and/or maintenance of the paternal epigenotype. We show here that a 0.9-kb deletion of exon 1 of mouse Snrpn did not disrupt imprinting or elicit any obvious phenotype, although it did allow the detection of previously unknown upstream exons. In contrast, a larger, overlapping 4.8-kb deletion caused a partial or mosaic imprinting defect and perinatal lethality when paternally inherited.     

Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor

Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. In contrast, it is unclear if the PACAP-PAC1 receptor pathway has a role in human psychological stress responses, such as post-traumatic stress disorder (PTSD). Here we find, in heavily traumatized subjects, a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females. We examined 44 single nucleotide polymorphisms (SNPs) spanning the PACAP (encoded by ADCYAP1) and PAC1 (encoded by ADCYAP1R1) genes, demonstrating a sex-specific association with PTSD. A single SNP in a putative oestrogen response element within ADCYAP1R1, rs2267735, predicts PTSD diagnosis and symptoms in females only. This SNP also associates with fear discrimination and with ADCYAP1R1 messenger RNA expression in human brain. Methylation of ADCYAP1R1 in peripheral blood is also associated with PTSD. Complementing these human data, ADCYAP1R1 mRNA is induced with fear conditioning or oestrogen replacement in rodent models. These data suggest that perturbations in the PACAP-PAC1 pathway are involved in abnormal stress responses underlying PTSD. These sex-specific effects may occur via oestrogen regulation of ADCYAP1R1. PACAP levels and ADCYAP1R1 SNPs may serve as useful biomarkers to further our mechanistic understanding of PTSD.