NEURAL ROSETTES FORMATION AS A NEWLY EMERGENT HUNTINGTIN FUNCTION

Huntingtin is a large, ubiquitous, partially unknown protein, in which mutation in its N-terminus is the cause of genetic, neurodegenerative disease called Huntington Disease. Although the presence of mutated huntingtin, from one decade it is known that the loss of wild-type protein can contribute to pathogenesis of HD (Cattaneo et al 2000). Huntingtin is embryonic lethal during embryogenesis and it exerts a fundamental role in the adult brain as a protein sustaining viability and health of mature neurons. Huntingtin is shown to be involved in neuron viability and maintenance, but its really and univocal function is already unknown. This study, object of my PhD project is focused on understand normal huntingtin function. Firstly, through a bioinformatic study by multialignment of 17 different homologues of huntingtin, both in deuterostome and protostome branches, we dissect the primary aminoacid sequence of huntingtin to reveal the presence of protein domains. The C-terminal portion of the protein proved to be conserved during evolution, while the N-terminal tract exhibited more recent evolution of the sequence. Moreover, look at the particular evolution and specification of the nervous system structures, and complexity along deuterostomes, we speculate that the evolution of the primary huntingtin aminoacid sequence parallels the particular evolution of the nervous system. In this view huntingtin could have evolved during phylogenesis a particular neural function. Furthermore, we study the role of normal huntingtin since its early embryonic function, in particular during the early phases of neural development, by using embryonic stem cell model. To dissect how this function is acquired during phylogenesis we choose to study neural differentiation process and the activity of the N-terminal domain during neurulation. We demonstrated that: i) huntingtin has a key role in the formation of neural tube-like rosettes, since its absence lead to a severe disorganization of neural precursors cells. ii) This defect is due to an impaired cell-cell adhesion mechanism, mediated by N-cadherin. iii) This function has emerged during deuterostomes evolution and it is exerted by the huntingtin N-terminal domain

Network sensitivity of systemic risk

A growing body of studies on systemic risk in financial markets has emphasized the key importance of taking into consideration the complex interconnections among financial institutions. Much effort has been put into modeling the contagion dynamics of financial shocks and into assessing the resilience of specific financial markets, either using real network data, reconstruction techniques or simple toy networks. Here, we address the more general problem of how shock propagation dynamics depend on the topological details of the underlying network. To this end, we consider different realistic network topologies, all consistent with balance sheet information obtained from real data on financial institutions. In particular, we consider networks of varying density and with different block structures. In addition, we diversify in the details of the shock propagation dynamics. We confirm that the systemic risk properties of a financial network are extremely sensitive to its network features. Our results can aid in the design of regulatory policies to improve the robustness of financial markets

Phylogenetic comparison of huntingtin homologues reveals the appearance of a primitive polyQ in sea urchin

Huntingtin is a completely soluble 3,144 amino acid (aa) protein characterized by the presence of an amino-terminal polymorphic polyglutamine (polyQ) tract, whose aberrant expansion causes the progressively neurodegenerative Huntington's disease (HD). Biological evidence indicates that huntingtin (htt) is beneficial to cells (particularly to brain neurons) and that loss of its neuronal function may contribute to HD. The exact protein domains involved in its neuroprotective function are unknown. Evolutionary analyses of htt primary aa have so far been limited to a few species, but its thorough assessment may help to clarify the functions emerging during evolution. We made an extensive comparative analysis of the available htt protein homologues from different organisms along the metazoan phylogenetic tree and defined the presence of 3 different conservative blocks corresponding to human htt aa 1-386 (htt1), 683-1,586 (htt2), and 2,437-3,078 (htt3), in which HEAT (Huntingtin, Elongator factor3, the regulatory A subunit of protein phosphatase 2A, and TOR1) repeats are well conserved. We also describe the cloning and sequencing of sea urchin htt mRNA, the oldest deuterostome homologue so far available. Multiple alignment shows the first appearance of a primitive polyQ in sea urchin, which predates an ancestral polyQ sequence in a nonchordate environment and defines the polyQ characteristic as being typical of the deuterostome branch. The fact that glutamines have conserved positions in deuterostomes and the polyQ size increases during evolution suggests that the protein has a possibly Q-dependent role. Finally, we report an evident relaxing constraint of the N-terminal block in Ciona and drosophilids that correlates with the absence of polyQ and which may indicate that the N-terminal portion of htt has evolved different functions in Ciona and protostome

Aberrant transcriptional and post-transcriptional regulation of SPAG5, a YAP-TAZ-TEAD downstream effector, fuels breast cancer cell proliferation

Sperm-associated antigen 5 (SPAG5) is an important driver of the cell mitotic spindle required for chromosome segregation and progression into anaphase. SPAG5 has been identified as an important proliferation marker and chemotherapy-sensitivity predictor, especially in estrogen receptor-negative breast cancer subtypes. Here, we report that SPAG5 is a direct target of miR-10b-3p, and its aberrantly high expression associates with poor disease-free survival in two large cohorts of breast cancer patients. SPAG5 depletion strongly impaired cancer cell cycle progression, proliferation, and migration. Interestingly, high expression of SPAG5 pairs with a YAP/TAZ-activated signature in breast cancer patients. Reassuringly, the depletion of YAP, TAZ, and TEAD strongly reduced SPAG5 expression and diminished its oncogenic effects. YAP, TAZ coactivators, and TEAD transcription factors are key components of the Hippo signaling pathway involved in tumor initiation, progression, and metastasis. Furthermore, we report that SPAG5 is a direct transcriptional target of TEAD/YAP/TAZ, and pharmacological targeting of YAP and TAZ severely reduces SPAG5 expression. Collectively, our data uncover an oncogenic feedback loop, comprising miR-10b-3p, SPAG5, and YAP/TAZ/TEAD, which fuels the aberrant proliferation of breast cancer

Folic Acid Exposure Rescues Spina Bifida Aperta Phenotypes in Human Induced Pluripotent Stem Cell Model

Neural tube defects (NTDs) are severe congenital abnormalities, caused by failed closure of neural tube during early embryonic development. Periconceptional folic acid (FA) supplementation greatly reduces the risk of NTDs. However, the molecular mechanisms behind NTDs and the preventive role of FA remain unclear. Here, we use human induced pluripotent stem cells (iPSCs) derived from fetuses with spina bifida aperta (SBA) to study the pathophysiology of NTDs and explore the effects of FA exposure. We report that FA exposure in SBA model is necessary for the proper formation and maturation of neural tube structures and robust differentiation of mesodermal derivatives. Additionally, we show that the folate antagonist methotrexate dramatically affects the formation of neural tube structures and FA partially reverts this aberrant phenotype. In conclusion, we present a novel model for human NTDs and provide evidence that it is a powerful tool to investigate the molecular mechanisms underlying NTDs, test drugs for therapeutic approaches

Valorizzazione del territorio di Corleone (PA) sfruttando il potenziale enologico di uve della cultivar “Catarratto”: prove realizzate su tre tipi podologici.

Gli Autori dopo aver descritto l'ambiente in cui si trovano i vigneti sperimentali passano ad analizzare la tecnica di gestione e la risposta produttiva

Macroscopic differences in HMGA oncoproteins post-translational modifications:C-terminal phosphorylation of HMGA2 affects its DNA binding properties.

We have performed an LC/MS screening on several different cell lines to investigate HMGA proteins expression and their posttranslational modifications in order to detect distinctive modification patterns for each. Our analyses evidenced relevant macroscopic differences in the phosphorylation and methylation patterns of these proteins. These differences occur both within the HMGA family members and in the different cell types. Focusing on HMGA2, we have mapped its in vivo phosphorylation sites demonstrating that, similarly to the HMGA1 proteins, it is highly phosphorylated on the acidic C-terminal tail and that these modifications affect its DNA binding properties