The 5th Open Day at the Barcelona Biomedical Research Park (PRBB) opens this edition of El·lipse, the park’s monthly newspaper.
Other news include the celebration of the CRG 10th anniversary, new proteins important for cell division or for tumour growth, how stem cell dysfunction links cancer and ageing or a new drug against skin cancer. You will also learn about the “Jennifer Aniston” neurone from Rodrigo Quian, from the University of Leicester (UK), or about the effects of radiations from mobile phones on our health, a subject that Elisabeth Cardis (CREAL) and her group are studying.
Complex genetic disorders often involve multiple proteins interacting with each other, and pinpointing which of them are actually important for the disease is still challenging. Many computational approaches exploiting interaction network topology have been successfully applied to prioritize which individual genes may be involved in diseases, based on their proximity to known disease genes in the network.
In a paper published in PLoS One, Baldo Oliva, head of the Structural bioinformatics group at the GRIB (UPF–IMIM) and Emre Guney, have presented GUILD (Genes Underlying Inheritance Linked Disorders), a new genome-wide network-based prioritization framework. GUILD includes four novel algorithms that use protein-protein interaction data to predict gene-phenotype associations at genome-wide scale, and the authors have proved that they are comparable, or outperform, several known state-of-the-art similar approaches.
As a proof of principle, the authors have used GUILD to investigate top-ranking genes in Alzheimer’s disease (AD), diabetes and AIDS using disease-gene associations from various sources.
GUILD is freely available for download at http://sbi.imim.es/GUILD.php
Guney E, Oliva B. Exploiting Protein-Protein Interaction Networks for Genome-Wide Disease-Gene Prioritization. PLoS One. 2012;7(9):e43557
Research on human aging is a hot topic nowadays, due to a growing aging population and the consequent prevalence of aging-associated diseases such as Alzheimer’s, arthritis or cardiovascular diseases. Researchers at the CMRB review the use of human induced pluripotent stem cells (hiPSC) to study the fundamental mechanisms underlying aging in this article published in Current Opinion in Cell Biology.
Indeed, hiPSC-based models of aging and aging-related diseases are facilitating the study of the molecular and cellular mechanisms underlying aging. For example, the use of iPSCs from patients with accelerated aging (like those with Hutchinson–Gilford progeria syndrome) could recapitulate the aging process in vitro much faster than the several decades needed for normal human tissue to age. Also, cell and organ derivatives from patient-specific iPSCs can be transplanted into animal models and the integrated human living materials could provide an opportunity to study human tissue and organ aging or disorders in an in vivo context.
Liu GH, Ding Z, Izpisua Belmonte JC. iPSC technology to study human aging and aging-related disorders. Curr Opin Cell Biol. 2012 Sep 18;
Amyloids – insoluble fibrous protein aggregates that share specific structural traits – are well known for their involvement in diseases such as Alzheimer’s, Parkinson’s, prions diseases and even diabetes 2 and some cancers. As evil as they seem, however, they also have a kinder side. Stavros Hamodrakas, head of the Biophysics and Bioinformatics laboratory at the Faculty of Biology, University of Athens (Greece), talked today at the PRBB about functional, non-pathogenic amyloids.
He actually was the first person to propose that the silk moth eggshell (or chorion) was a natural, protective amyloid. The chorion is a multi-layered structure that protects the egg from desiccation and infections and which provides thermal insulation.
Hamodrakas reviewed in this talk his research over the last 30 years on this field. Since those first days, many more examples of protective amyloids have been found, from bacteria to human – including the covers of the eggs of many species such as fish, mouse and humans. Skipping through all the details, the conclusion was that tandem hexapeptide repeats present in the aminoacid sequence of the central domain of chorion proteins is what dictates the folding and self-assembly of those amyloid-like protein. One peculiarity he mentioned was the fact that all the proteins that form amyloids are very different amongst them at the sequence level. However, the structure – the focus of Hamodrakas’ research – has similarities.
The audience was very involved in the talk, and an interesting debate originated afterwards around the question: why are some amyloids functional, protective either, and others pathological? One of the potential answers is the fact that all protective amyloids are extracellular, so they don’t affect the functioning of the cell. And even thought they were synthesized within the cell, they were ‘protected’ within vesicles until they were secreted.
There’s still a lot to learn about protective amyloids, and the more we know about them, the better we can understand the pathological ones.
Report by Maruxa Martinez, Scientific Editor at the PRBB
“Alzheimer’s is the price we pay for a life of thinking” – Ageing brain research group of the CEXS-UPF
All four of the PhD students in the ageing brain research group of the CEXS-UPF studied biology at the UPF. “It is our direct source of students!”, says Paco Muñoz López, head of the group and professor at that university. A postdoctoral researcher completes the group, which focuses on nitro-oxidative stress and its link to Alzheimer’s disease.
“The most important risk factor in Alzheimer’s disease is age –says Muñoz–. About 10% of the population over 65 suffer Alzheimer’s, but the percentage goes up to 50% in over 80 year-olds. I think it’s just the price to pay for a life of thinking, a consequence of the overuse of our neurones”. There are also genetic factors, but less than 3% of the cases are familial, mostly due to mutations in APP (amyloid precursor protein) and presenilins.
An aggregation problem
At a molecular level, Alzheimer’s is triggered by the accumulation of amyloid ß-peptide (Aß) aggregates in the brain, in particular in the hippocampus and the cortex. The Aß is a subproduct of the processing of APP, a ubiquitous protein of unknown function. Muñoz’s group suggests that it is a key protein in memory and learning processes.
In other parts of the body, the soluble Aß is eliminated through the liver, but in the case of the brain it cannot pass the bloodbrain barrier and therefore it accumulates. “Once it aggregates the problem starts”, says Muñoz. The group tries to understand how and when APP is processed by BACE1, the enzyme that generates Aß from APP, as well as the role of nitroxidative stress in BACE1 activation and Aß neurotoxicity. When the Aß aggregates it produces free radicals which react with the neuronal nitric oxide, generating peroxynitrite, a very reactive anion that harms proteins.
On the other hand, Aß oligomers bind different membrane proteins, in particular NMDA, a huge receptor for glutamate that, when opened, lets Ca2+ into the cell. When Aß amyloid binds NMDA, it forces the receptor to be half open all the time. This allows a constant flux of Ca2+ into the neurone which, slowly, kills it. The inhibition of the NMDA receptor has been proposed as a specific treatment to slow down Alzheimer’s. But there are other proteins that could pave the way to new therapeutic targets.
One of these was pinpointed by Muñoz’s group in a study that took them four years. “We added Aß to cell cultures and then did some proteomic analyses to determine which proteins had been nitrated. One of them was TPI, a key glycolytic enzyme. Interestingly, glucose consumption in the neurones of people with Alzheimer’s is lower than normal, and it wasn’t known why”, explains the biologist. They looked in APP and presenilin transgenic mice and in brains of Alzheimer’s patients. In both cases they saw that TPI was nitrated. The biochemical studies that followed and some computational studies done by colleagues at the GRIB (UPF-IMIM) confirmed that, when nitrated, TPI was less active. A three-month stay in Japan followed, where Muñoz cloned the TPI enzyme. Finally, they were able to show by electron microscopy that the nitrated TPI aggregated within the cell.
“So far we have focused on the pathological role of APP. But in the near future I want to understand the physiological role of APP in memory, something that remains a mystery”, concludes Muñoz.
This article was published in the El·lipse publication