Amyloid-Mediated Sequestration of Essential Proteins Contributes to Mutant Huntingtin Toxicity in Yeast

BACKGROUND: Polyglutamine expansion is responsible for several neurodegenerative disorders, among which Huntington disease is the most well-known. Studies in the yeast model demonstrated that both aggregation and toxicity of a huntingtin (htt) protein with an expanded polyglutamine region strictly depend on the presence of the prion form of Rnq1 protein ([PIN+]), which has a glutamine/asparagine-rich domain. PRINCIPAL FINDINGS: Here, we showed that aggregation and toxicity of mutant htt depended on [PIN+] only quantitatively: the presence of [PIN+] elevated the toxicity and the levels of htt detergent-insoluble polymers. In cells lacking [PIN+], toxicity of mutant htt was due to the polymerization and inactivation of the essential glutamine/asparagine-rich Sup35 protein and related inactivation of another essential protein, Sup45, most probably via its sequestration into Sup35 aggregates. However, inhibition of growth of [PIN+] cells depended on Sup35/Sup45 depletion only partially, suggesting that there are other sources of mutant htt toxicity in yeast. CONCLUSIONS: The obtained data suggest that induced polymerization of essential glutamine/asparagine-rich proteins and related sequestration of other proteins which interact with these polymers represent an essential source of htt toxicity

Antioxidant intake among Brazilian adults - The Brazilian Osteoporosis Study (BRAZOS): a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Antioxidant nutrient intake and the lesser formation of free radicals seem to contribute to chronic diseases. The aim of the present study was to evaluate the intake profile of the main dietary antioxidants in a representative sample of the adult Brazilian population and discuss the main consequences of a low intake of these micronutrients on overall health.</p> <p>Methods</p> <p>The sample comprised 2344 individuals aged 40 years or older from 150 cities and was based on a probabilistic sample from official data. The research was conducted through in-home interviews administered by a team trained for this purpose. Dietary intake information was obtained through 24-h recall. The Nutrition Data System for Research software program was used to analyze data on the intake of vitamins A, C and E, selenium and zinc, which was compared to Dietary Reference Intakes (DRIs). Differences in intake according to sex, anthropometrics, socioeconomic status and region were also evaluated. The SPSS statistical package (version 13) was used for the statistical analysis. P-values < 0.05 were considered significant.</p> <p>Results</p> <p>Higher proportions of low intake in relation to recommended values were found for vitamin E (99.7%), vitamin A (92.4%) and vitamin C (85.1%) in both genders. Intake variations were found between different regions, which may reflect cultural habits.</p> <p>Conclusion</p> <p>These results should lead to the development of public health policies that encourage educational strategies for improving the intake of micronutrients, which are essential to overall health and prevention of non-communicable diseases.</p

Imaging the Impact of Prenatal Alcohol Exposure on the Structure of the Developing Human Brain

Prenatal alcohol exposure has numerous effects on the developing brain, including damage to selective brain structure. We review structural magnetic resonance imaging (MRI) studies of brain abnormalities in subjects prenatally exposed to alcohol. The most common findings include reduced brain volume and malformations of the corpus callosum. Advanced methods have been able to detect shape, thickness and displacement changes throughout multiple brain regions. The teratogenic effects of alcohol appear to be widespread, affecting almost the entire brain. The only region that appears to be relatively spared is the occipital lobe. More recent studies have linked cognition to the underlying brain structure in alcohol-exposed subjects, and several report patterns in the severity of brain damage as it relates to facial dysmorphology or to extent of alcohol exposure. Future studies exploring relationships between brain structure, cognitive measures, dysmorphology, age, and other variables will be valuable for further comprehending the vast effects of prenatal alcohol exposure and for evaluating possible interventions

Function of SSA Subfamily of Hsp70 Within and Across Species Varies Widely in Complementing Saccharomyces cerevisiae Cell Growth and Prion Propagation

BACKGROUND:The cytosol of most eukaryotic cells contains multiple highly conserved Hsp70 orthologs that differ mainly by their spatio-temporal expression patterns. Hsp70s play essential roles in protein folding, transport or degradation, and are major players of cellular quality control processes. However, while several reports suggest that specialized functions of Hsp70 orthologs were selected through evolution, few studies addressed systematically this issue. METHODOLOGY/PRINCIPAL FINDINGS:We compared the ability of Ssa1p-Ssa4p from Saccharomyces cerevisiae and Ssa5p-Ssa8p from the evolutionary distant yeast Yarrowia lipolytica to perform Hsp70-dependent tasks when expressed as the sole Hsp70 for S. cerevisiae in vivo. We show that Hsp70 isoforms (i) supported yeast viability yet with markedly different growth rates, (ii) influenced the propagation and stability of the [PSI(+)] and [URE3] prions, but iii) did not significantly affect the proteasomal degradation rate of CFTR. Additionally, we show that individual Hsp70 orthologs did not induce the formation of different prion strains, but rather influenced the aggregation properties of Sup35 in vivo. Finally, we show that [URE3] curing by the overexpression of Ydj1p is Hsp70-isoform dependent. CONCLUSION/SIGNIFICANCE:Despite very high homology and overlapping functions, the different Hsp70 orthologs have evolved to possess distinct activities that are required to cope with different types of substrates or stress situations. Yeast prions provide a very sensitive model to uncover this functional specialization and to explore the intricate network of chaperone/co-chaperone/substrates interactions

PAK4 signaling in development and cancer

Our understanding of cancer biology has been evolving rapidly shaped by groundbreaking discoveries. We now understand that cancer is not one disease but many, and that tumors are not foreign objects in the human body but rather the result of changes in the previously normal tissues and organs. Thus, in order to ask fundamental questions and dissect the complexity of cancer it is essential to grasp how the healthy organs develop and function and the cellular and molecular mechanisms involved. The serine/threonine PAKs are signaling hubs with proven roles in development and disease. Specifically, they are important to several hallmarks of cancer. Thus, the family in general, and PAK4 in particular, is increasingly attracting the interest of the scientific community. In this thesis I have explored the role of PAK4 in normal organ development and cancer. Novel mouse models with PAK4 depletion in the mammary gland and in the pancreas have been established and characterized in Paper I and Paper II. The absence of major tissue abnormalities upon PAK4 depletion in the mammary epithelium allowed me to use this model to study the role of PAK4 in tumorigenesis in vivo, in Paper III, and a counterpart mouse model with PAK4 overexpression in the mammary epithelium was also generated. These complementary in vivo setups showed that PAK4-overexpressing mammary glands occasionally developed mammary tumors while PAK4 abrogation impaired PyMT-driven mammary tumorigenesis. Extensive in vitro experiments, using state of the art techniques, then supported a model in which PAK4 confers selective advantages to cancer cells by overcoming the senescence barrier. This, in turn, constitutes a selective vulnerability of cancer cells that become susceptible to a senescence-like response upon PAK4 inhibition. The data presented also demonstrates a crosstalk between PAK4 and NF-κB signaling, and a direct interaction and phosphorylation site within the REL-homology domain of RELB is found to be relevant for tuning RELB-mediated transcription and cancer cell proliferation via C/EBPβ. Importantly, these findings were largely supported by correlations in clinical data and validated ex vivo in patient-derived cells, thus highlighting PAK4 as an attractive therapeutic opportunity in cancer. Therefore, this thesis contributes to a better understanding of the mechanisms that govern breast tumorigenesis, with hopes that such knowledge will prove relevant in cancer prognosis and treatment

The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio

Exploration of Shared Genetic Architecture Between Subcortical Brain Volumes and Anorexia Nervosa

In MRI scans of patients with anorexia nervosa (AN), reductions in brain volume are often apparent. However, it is unknown whether such brain abnormalities are influenced by genetic determinants that partially overlap with those underlying AN. Here, we used a battery of methods (LD score regression, genetic risk scores, sign test, SNP effect concordance analysis, and Mendelian randomization) to investigate the genetic covariation between subcortical brain volumes and risk for AN based on summary measures retrieved from genome-wide association studies of regional brain volumes (ENIGMA consortium, n = 13,170) and genetic risk for AN (PGC-ED consortium, n = 14,477). Genetic correlations ranged from − 0.10 to 0.23 (all p > 0.05). There were some signs of an inverse concordance between greater thalamus volume and risk for AN (permuted p = 0.009, 95% CI: [0.005, 0.017]). A genetic variant in the vicinity of ZW10, a gene involved in cell division, and neurotransmitter and immune system relevant genes, in particular DRD2, was significantly associated with AN only after conditioning on its association with caudate volume (pFDR = 0.025). Another genetic variant linked to LRRC4C, important in axonal and synaptic development, reached significance after conditioning on hippocampal volume (pFDR = 0.021). In this comprehensive set of analyses and based on the largest available sample sizes to date, there was weak evidence for associations between risk for AN and risk for abnormal subcortical brain volumes at a global level (that is, common variant genetic architecture), but suggestive evidence for effects of single genetic markers. Highly powered multimodal brain- and disorder-related genome-wide studies are needed to further dissect the shared genetic influences on brain structure and risk for AN

Loss of a Conserved tRNA Anticodon Modification Perturbs Plant Immunity

[EN] tRNA is the most highly modified class of RNA species, and modifications are found in tRNAs from all organisms that have been examined. Despite their vastly different chemical structures and their presence in different tRNAs, occurring in different locations in tRNA, the biosynthetic pathways of the majority of tRNA modifications include a methylation step(s). Recent discoveries have revealed unprecedented complexity in the modification patterns of tRNA, their regulation and function, suggesting that each modified nucleoside in tRNA may have its own specific function. However, in plants, our knowledge on the role of individual tRNA modifications and how they are regulated is very limited. In a genetic screen designed to identify factors regulating disease resistance and activation of defenses in Arabidopsis, we identified SUPPRESSOR OF CSB3 9 (SCS9). Our results reveal SCS9 encodes a tRNA methyltransferase that mediates the 2'-O-ribose methylation of selected tRNA species in the anticodon loop. These SCS9-mediated tRNA modifications enhance during the course of infection with the bacterial pathogen Pseudomonas syringae DC3000, and lack of such tRNA modification, as observed in scs9 mutants, severely compromise plant immunity against the same pathogen without affecting the salicylic acid (SA) signaling pathway which regulates plant immune responses. Our results support a model that gives importance to the control of certain tRNA modifications for mounting an effective immune response in Arabidopsis, and therefore expands the repertoire of molecular components essential for an efficient disease resistance response.This work was supported by the National Science Foundation of China (grant 31100268 to PC) and the Spanish MINECO (BFU2012 to PV) and Generalitat Valenciana (Prometeo2014/020 to PV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ramirez Garcia, V.; González-García, B.; López Sánchez, A.; Castelló Llopis, MJ.; Gil, M.; Zheng, B.; Cheng, P.... (2015). Loss of a Conserved tRNA Anticodon Modification Perturbs Plant Immunity. PLoS Genetics. 11(10):1-27. https://doi.org/10.1371/journal.pgen.1005586S127111