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.

Pleiotrophin over-expression provides trophic support to dopaminergic neurons in parkinsonian rats.

Abstract: Background Pleiotrophin is known to promote the survival and differentiation of dopaminergic neurons in vitro and is up-regulated in the substantia nigra of Parkinson's disease patients. To establish whether pleiotrophin has a trophic effect on nigrostriatal dopaminergic neurons in vivo, we injected a recombinant adenovirus expressing pleiotrophin in the substantia nigra of 6-hydroxydopamine lesioned rats.

Transition state for protein-DNA recognition.

Abstract: We describe the formation of protein-DNA contacts in the two-state route for DNA sequence recognition by a transcriptional regulator. Surprisingly, direct sequence readout establishes in the transition state and constitutes the bottleneck of complex formation. Although a few nonspecific ionic interactions are formed at this early stage, they mainly play a stabilizing role in the final consolidated complex. The interface is fairly plastic in the transition state, likely because of a high level of hydration. The overall picture of this two-state route largely agrees with a smooth energy landscape for binding that speeds up DNA recognition. This "direct" two-state route differs from the parallel multistep pathway described for this system, which involves nonspecific contacts and at least two intermediate species that must involve substantial conformational rearrangement in either or both macromolecules.

The Sesquiterpene Lactone Dehydroleucodine Triggers Senescence and Apoptosis in Association with Accumulation of DNA Damage Markers

Abstract: Sesquiterpene lactones (SLs) are plant-derived compounds that display anti-cancer effects. Some SLs derivatives have a marked killing effect on cancer cells and have therefore reached clinical trials. Little is known regarding the mechanism of action of SLs. We studied the responses of human cancer cells exposed to various concentrations of dehydroleucodine (DhL), a SL of the guaianolide group isolated and purified from Artemisia douglasiana (Besser), a medicinal herb that is commonly used in Argentina. We demonstrate for the first time that treatment of cancer cells with DhL, promotes the accumulation of DNA damage markers such as phosphorylation of ATM and focal organization of γH2AX and 53BP1. This accumulation triggers cell senescence or apoptosis depending on the concentration of the DhL delivered to cells. Transient DhL treatment also induces marked accumulation of senescent cells. Our findings help elucidate the mechanism whereby DhL triggers cell cycle arrest and cell death and provide a basis for further exploration of the effects of DhL in in vivo cancer treatment models.

Synaptic control of mRNA translation by reversible assembly of XRN1 bodies

Abstract: Repression of mRNA translation is linked to the formation of specific cytosolic foci such as stress granules and processing bodies, which store or degrade mRNAs. In neurons, synaptic activity regulates translation at the post‐synapse and this is important for plasticity. N‐methyl‐D‐aspartate (NMDA) receptor stimulation downregulates translation, and we speculate that this is linked to the formation of unknown mRNA‐silencing foci. Here, we show that the 5′‐3′ exoribonuclease XRN1 forms discrete clusters associated with the post‐synapse that are different from processing bodies or stress granules, and we named them synaptic XRN1 bodies (SX‐bodies). Using primary neurons, we found that the SX‐bodies respond to synapse stimulation and that their formation correlates inversely with the local translation rate. SX‐bodies increase in size and number upon NMDA stimulation, and metabotropic glutamate receptor activation provokes SX‐body dissolution, along with increased translation. The response is specific and the previously described Smaug1 foci and FMRP granules show a different response. Finally, XRN1 knockdown impairs the translational repression triggered by NMDA. Collectively, these observations support a role for the SX‐bodies in the reversible masking and silencing of mRNAs at the synapse.

Short linear motif core and flanking regions modulate retinoblastoma protein binding affinity and specificity.

Abstract: Pocket proteins retinoblastoma (pRb), p107 and p130 are negative regulators of cellular proliferation and multifunctional proteins regulating development, differentiation and chromatin structure. The retinoblastoma protein is a potent tumor suppressor mutated in a wide range of human cancers, and oncogenic viruses often interfere with cell cycle regulation by inactivating pRb. The LxCxE and pRb AB groove short linear motifs (SLiMs) are key to many pocket protein mediated interactions including host and viral partners. A review of available experimental evidence reveals that several core residues composing each motif instance are determinants for binding. In the LxCxE motif, a fourth hydrophobic position that might allow variable spacing is required for binding. In both motifs, flanking regions including charged stretches and phosphorylation sites can fine-tune the binding affinity and specificity of pocket protein SLiM-mediated interactions. Flanking regions can modulate pocket protein binding specificity, or tune the high affinity interactions of viral proteins that hijack the pRb network. The location of SLiMs within intrinsically disordered regions allows faster evolutionary rates that enable viruses to acquire a functional variant of the core motif by convergent evolution, and subsequently test numerous combinations of flanking regions towards maximizing interaction specificity and affinity. This knowledge can guide future efforts directed at the design of peptide-based compounds that can target pocket proteins to regulate the G1/S cell cycle checkpoint or impair viral mediated pRb inactivation.