HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS

A prominent feature of late-onset neurodegenerative diseases is accumulation of misfolded protein in vulnerable neurons. When levels of misfolded protein overwhelm degradative pathways, the result is cellular toxicity and neurodegeneration. Cellular mechanisms for degrading misfolded protein include the ubiquitin-proteasome system (UPS), the main non-lysosomal degradative pathway for ubiquitinated proteins, and autophagy, a lysosome-mediated degradative pathway. The UPS and autophagy have long been viewed as complementary degradation systems with no point of intersection. This view has been challenged by two observations suggesting an apparent interaction: impairment of the UPS induces autophagy in vitro, and conditional knockout of autophagy in the mouse brain leads to neurodegeneration with ubiquitin-positive pathology. It is not known whether autophagy is strictly a parallel degradation system, or whether it is a compensatory degradation system when the UPS is impaired; furthermore, if there is a compensatory interaction between these systems, the molecular link is not known. Here we show that autophagy acts as a compensatory degradation system when the UPS is impaired in Drosophila melanogaster, and that histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase that interacts with polyubiquitinated proteins, is an essential mechanistic link in this compensatory interaction. We found that compensatory autophagy was induced in response to mutations affecting the proteasome and in response to UPS impairment in a fly model of the neurodegenerative disease spinobulbar muscular atrophy. Autophagy compensated for impaired UPS function in an HDAC6-dependent manner. Furthermore, expression of HDAC6 was sufficient to rescue degeneration associated with UPS dysfunction in vivo in an autophagy-dependent manner. This study suggests that impairment of autophagy (for example, associated with ageing or genetic variation) might predispose to neurodegeneration. Morover, these findings suggest that it may be possible to intervene in neurodegeneration by augmenting HDAC6 to enhance autophagy.     

Large subglacial lakes in East Antarctica at the onset of fast-flowing ice streams

Water plays a crucial role in ice-sheet stability and the onset of ice streams. Subglacial lake water moves between lakes and rapidly drains, causing catastrophic floods. The exact mechanisms by which subglacial lakes influence ice-sheet dynamics are unknown, however, and large subglacial lakes have not been closely associated with rapidly flowing ice streams. Here we use satellite imagery and ice-surface elevations to identify a region of subglacial lakes, similar in total area to Lake Vostok, at the onset region of the Recovery Glacier ice stream in East Antarctica and predicted by ice-sheet models. We define four lakes through extensive, flat, featureless regions of ice surface bounded by upstream troughs and downstream ridges. Using ice velocities determined using interferometric synthetic aperture radar (InSAR), we find the onset of rapid flow (moving at 20 to 30 m yr(-1)) of the tributaries to the Recovery Glacier ice stream in a 280-km-wide segment at the downslope margins of these four subglacial lakes. We conclude that the subglacial lakes initiate and maintain rapid ice flow through either active modification of the basal thermal regime of the ice sheet by lake accretion or through scouring bedrock channels in periodic drainage events. We suggest that the role of subglacial lakes needs to be considered in ice-sheet mass balance assessments.     

East Antarctic rifting triggers uplift of the Gamburtsev Mountains

The Gamburtsev Subglacial Mountains are the least understood tectonic feature on Earth, because they are completely hidden beneath the East Antarctic Ice Sheet. Their high elevation and youthful Alpine topography, combined with their location on the East Antarctic craton, creates a paradox that has puzzled researchers since the mountains were discovered in 1958. The preservation of Alpine topography in the Gamburtsevs may reflect extremely low long-term erosion rates beneath the ice sheet, but the mountains' origin remains problematic. Here we present the first comprehensive view of the crustal architecture and uplift mechanisms for the Gamburtsevs, derived from radar, gravity and magnetic data. The geophysical data define a 2,500-km-long rift system in East Antarctica surrounding the Gamburtsevs, and a thick crustal root beneath the range. We propose that the root formed during the Proterozoic assembly of interior East Antarctica (possibly about 1 Gyr ago), was preserved as in some old orogens and was rejuvenated during much later Permian (roughly 250 Myr ago) and Cretaceous (roughly 100 Myr ago) rifting. Much like East Africa, the interior of East Antarctica is a mosaic of Precambrian provinces affected by rifting processes. Our models show that the combination of rift-flank uplift, root buoyancy and the isostatic response to fluvial and glacial erosion explains the high elevation and relief of the Gamburtsevs. The evolution of the Gamburtsevs demonstrates that rifting and preserved orogenic roots can produce broad regions of high topography in continental interiors without significantly modifying the underlying Precambrian lithosphere.     

Structure and function of Zika virus NS5 protein: perspectives for drug design

Zika virus (ZIKV) belongs to the positive-sense single-stranded RNA-containing Flaviviridae family. Its recent outbreak and association with human diseases (e.g. neurological disorders) have raised global health concerns, and an urgency to develop a therapeutic strategy against ZIKV infection. However, there is no currently approved antiviral against ZIKV. Here we present a comprehensive overview on recent progress in structure–function investigation of ZIKV NS5 protein, the largest non-structural protein of ZIKV, which is responsible for replication of the viral genome, RNA capping and suppression of host interferon responses. Structural comparison of the N-terminal methyltransferase domain and C-terminal RNA-dependent RNA polymerase domain of ZIKV NS5 with their counterparts from related viruses provides mechanistic insights into ZIKV NS5-mediated RNA replication, and identifies residues critical for its enzymatic activities. Finally, a collection of recently identified small molecule inhibitors against ZIKV NS5 or its closely related flavivirus homologues are also discussed.     

Common variants at 12q14 and 12q24 are associated with hippocampal volume

Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.     

Glutamate transporters in the biology of malignant gliomas

Malignant gliomas are relentless tumors that offer a dismal clinical prognosis. They develop many biological advantages that allow them to grow and survive in the unique environment of the brain. The glutamate transporters system x _c ^? and excitatory amino acid transporters (EAAT) are emerging as key players in the biology and malignancy of these tumors. Gliomas manipulate glutamate transporter expression and function to alter glutamate homeostasis in the brain, which supports their own growth, invasion, and survival. As a consequence, malignant cells are able to quickly destroy and invade surrounding normal brain. Recent findings are painting a larger picture of these transporters in glioma biology, and as such are providing opportunities for clinical intervention for patients. This review will detail the current understanding of glutamate transporters in the biology of malignant gliomas and highlight some of the unique aspects of these tumors that make them so devastating and difficult to treat.     

Chromosome boundary elements and regulation of heterochromatin spreading

Chromatin is generally classified as euchromatin or heterochromatin, each with distinct histone modifications, compaction levels, and gene expression patterns. Although the proper formation of heterochromatin is essential for maintaining genome integrity and regulating gene expression, heterochromatin can also spread into neighboring regions in a sequence-independent manner, leading to the inactivation of genes. Because the distance of heterochromatin spreading is stochastic, the formation of boundaries, which block the spreading of heterochromatin, is critical for maintaining stable gene expression patterns. Here we review the current understanding of the mechanisms underlying heterochromatin spreading and boundary formation.