Fundación Instituto Leloir

About: Fundación Instituto Leloir is a facility organization based out in Buenos Aires, Argentina. It is known for research contribution in the topics: Dentate gyrus & Neurogenesis. The organization has 702 authors who have published 1052 publications receiving 39299 citations.

Kin-Driver: a database of driver mutations in protein kinases.

Abstract: Somatic mutations in protein kinases (PKs) are frequent driver events in many human tumors, while germ-line mutations are associated with hereditary diseases. Here we present Kin-driver, the first database that compiles driver mutations in PKs with experimental evidence demonstrating their functional role. Kin-driver is a manual expert-curated database that pays special attention to activating mutations (AMs) and can serve as a validation set to develop new generation tools focused on the prediction of gain-of-function driver mutations. It also offers an easy and intuitive environment to facilitate the visualization and analysis of mutations in PKs. Because all mutations are mapped onto a multiple sequence alignment, analogue positions between kinases can be identified and tentative new mutations can be proposed for studying by transferring annotation. Finally, our database can also be of use to clinical and translational laboratories, helping them to identify uncommon AMs that can correlate with response to new antitumor drugs. The website was developed using PHP and JavaScript, which are supported by all major browsers; the database was built using MySQL server. Kin-driver is available at: http://kin-driver.leloir.org.ar/

Presenilin-1 280Glu-->Ala mutation alters C-terminal APP processing yielding longer abeta peptides: implications for Alzheimer's disease.

Abstract: Presenilin (PS) mutations enhance the production of the Abeta42 peptide that is derived from the amyloid precursor protein (APP) The pathway(s) by which the Abeta42 species is preferentially produced has not been elucidated, nor is the mechanism by which PS mutations produce early-onset dementia established Using a combination of histological, immunohistochemical, biochemical, and mass spectrometric methods, we examined the structural and morphological nature of the amyloid species produced in a patient expressing the PS1 280Glu-->Ala familial Alzheimer's disease mutation Abundant diffuse plaques were observed that exhibited a staining pattern and morphology distinct from previously described PS cases, as well as discreet amyloid plaques within the white matter In addition to finding increased amounts of CT99 and Abeta42 peptides, our investigation revealed the presence of a complex array of Abeta peptides substantially longer than 42/43 amino acid residue species The increased hydrophobic nature of longer Abeta species retained within the membrane walls could impact the structure and function of plasma membrane and organelles These C-terminally longer peptides may, through steric effects, dampen the rate of turnover by critical amyloid degrading enzymes such as neprilysin and insulin degrading enzyme A complete understanding of the deleterious side effects of membrane bound Abeta as a consequence of gamma-secretase alterations is needed to understand Alzheimer's disease pathophysiology and will aid in the design of therapeutic interventions

Translation and silencing in RNA granules: a tale of sand grains

Abstract: The transcriptome at the synapse consists of thousands of messengers encoding several cellular functions, including a significant number of receptors and ion channels and associated proteins. The concerted translational regulation of all these molecules contributes to the dynamic control of synaptic strength. Cumulative evidence supports that dendritic RNA granules and mRNA-silencing foci play an important role in translational regulation. Several relevant RBPs - FMRP; FUS/TLS; TDP-43; Staufen; Smaug; Pumilio; CPEB; HuD; ZBP1; and DDX6 among others - form granules that contain dormant mRNAs repressed by multiple pathways. Recent reports indicate that dendritic granules may contain stalled polysomes, and furthermore, active translation may occur in association with RNA granules. Here, we discuss the molecules and pathways involved in this continuum of RNA granules that contain masked mRNAs, mRNAs trapped in inactive polysomes or mRNAs engaged in translation.

Alternative splicing at the right time.

Abstract: Alternative splicing (AS) allows the production of multiple mRNA variants from a single gene, which contributes to increase the complexity of the proteome. There is evidence that AS is regulated not only by auxiliary splicing factors, but also by components of the core spliceosomal machinery, as well as through epigenetic modifications. However, to what extent these different mechanisms contribute to the regulation of AS in response to endogenous or environmental stimuli is still unclear. Circadian clocks allow organisms to adjust physiological processes to daily changes in environmental conditions. Here we review recent evidence linking circadian clock and AS, and discuss the role of Protein Arginine Methyltransferase 5 (PRMT5) in these processes. We propose that the interactions between daily oscillations in AS and circadian rhythms in the expression of splicing factors and epigenetic regulators offer a great opportunity to dissect the contribution of these mechanisms to the regulation of AS in a physiologically relevant context.