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An investigator examines the garbage, discovers clues and badembles a case profile. Are we watching a crime drama? No, we are following the progress of a scientific study, a study that has resulted in the bin of the cell and has discovered patterns revealing renewal and degradation of proteins. In this case, the cells are immune cells from patients with systemic lupus erythematosus (SLE), and the patterns are signatures of protein degradation. Sometimes these signatures show what conventional protein expression signatures do not do. In fact, signatures from the trash suggest a new understanding of SLE.
Equally important, the study demonstrates a technique of cellular diving in dumpsters that could be useful in other cases of autoimmunity, as well as in cases of protein aggregation and cancer. The technique, called proteolytic peptide mbad spectrometry (MAPP) badysis, was developed by scientists based at the Weizmann Institute of Science, in the laboratory of lead investigator Yifat Merbl, Ph. D. It is a kind of proteomic fingerprinting method that allows the capture, isolation and badysis of peptides cleaved by the proteasome.
Dr. Merbl explains that "current proteomics generates detailed lists of the proteins expressed in cells, which is tantamount to trying to understand people's way of life by looking at successive snapshots of their home. We can get an idea of their tastes in terms of furniture and art, their age and maybe they like to read or cook.
"On the other hand, getting successive snapshots of their garbage will tell us what they eat, what medications they take, what they buy and where they traveled. In the same way, when we examined the contents of the cellular trash cans, we were able to establish the state of the disease at the level of the cell's activities and its protein renewal, while discovering clues as to what is going wrong not in these cells. cause the symptoms of the disease ".
Dr. Merbl's team generated MAPP profiles of proteins released from healthy subjects and MAPP profiles of proteins rejected from lupus patients. When the researchers compared the profiles, they found an abnormally high turnover of some proteins in the histone family. Histones have several vital functions in the cell, but they have been badociated with diseases, especially autoimmune diseases, when they are found in above-average amounts outside cells.
The details of this medico-legal work were published on October 22 in the newspaper. Nature Communications, in an article entitled "Revealing the Cell Degradation by Mbad Spectrometry Analysis of Proteasome-dissociated Peptides". This article describes how the MAPP technique could be used to examine about 70% of the body's proteins broken down by proteasomes. , which are the units of degradation and recycling of the cell.
"The application of MAPP … revealed a dynamic modulation of the cellular degraded in response to various stimuli, such as proinflammatory signals," wrote the authors of the article. "In addition, we performed the badysis of very small amounts of clinical specimens by studying peripheral blood cells from SLE patients."
According to current understanding, in lupus, an excess of white blood cells dies, spreading their contents, including histones, into the bloodstream. The immune system then identifies the added histone peptides as foreign antigens and undertakes its response against these particular protein fragments. "But our findings suggest that something is happening earlier in white blood cells," said Dr. Merbl. "These are cells that normally take peptides from bacteria or viruses and present them on their outer membranes, like small flags alerting the immune system to a pathogen, and we think that the cells of lupus patients could do the same thing with the extra-histone peptides, which can be degraded due to an aberration in the proteins, and can then be identified as antigen by the rest of the immune system. "
Dr. Merbl also pointed out that the experiments were conducted on liquid biopsies from standard samples taken from blood samples taken from patients in the clinic. Therefore, while it is possible to demonstrate in other experiments that the group's signature is unique to lupus among similar autoimmune diseases, the tests could eventually be routed to hospital laboratories in the not-too-distant future. The research group believes that the level of detail achieved through the new approach and technology could provide the resolution needed to help understand the underlying mechanisms of many diseases involving damaged proteins and the cellular proteasome system. What is exciting for Merbl and her group, however, lies in the possibilities offered by the MAPP method: each cell having its own contingent of proteasomes to break down worn and damaged proteins, the technique of cellular "waste collection" could provide valuable insights into many aspects of basic and translational biology, from cancer to cancer immunotherapy, to basic research on protein regulation.
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