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fight degenerative diseases

The proteins and mechanisms required to fight the protein accumulations that lead to neurodegenerative diseases have been identified

Left: cells with a mutant FUS protein that causes accumulations (in green) and leads to ALS disease. Right: the cells with the protein/chaferon (in pink) that manages to prevent the accumulations
Left: cells with a mutant FUS protein that causes accumulations (in green) and leads to ALS disease. Right: the cells with the protein/chaferon (in pink) that manages to prevent the accumulations

The body's proteins function and operate thanks to homeostasis in the cells - a state in which the physical and chemical conditions that suit their function and activity are maintained, despite changes in their external environment. Prof. Reot Sheligi from the Faculty of Medicine at the Technion researches together with her team, using molecular and computational biology, how the cells of the body maintain protein homeostasis in a normal state and in environmental or physiological stress situations.

"In stressful situations, the cells have to react very quickly to prevent damage to themselves and the proteins," says Prof. Shelgi. "They usually do it well because they are evolutionarily programmed for it. But when they are damaged (for example by mutation) and do not do this, diseases develop. For example, most neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's and ALS, are caused by problems in protein folding - the organization of the amino acid chains that make them up into a three-dimensional structure. That is, the proteins that cause the disease fold incorrectly, stick to each other and form accumulations (aggregation) that sink into nerve cells and destroy them. If we understand how to prevent this situation, we may be able to better fight these diseases."

To this end, Prof. Shelgi and her team simulate stress conditions in the cells in their laboratory and examine their systemic response. For example, what happens to the genes in them, which of them are expressed, which proteins are translated from them and what changes occur in their folding. In the latest study, which won a research grant from the National Science Foundation, doctoral students Kinneret Rosales and Amal Younis (research leaders) and Prof. Shelgi expressed, in human cell cultures, the HTT protein with a mutation that causes Huntington's and the FUS protein with a mutation that causes ALS.

Huntington's is a genetic disease characterized by motor, cognitive and psychiatric disorders and ALS is a terminal muscular dystrophy. In these diseases, the proteins HTT and FUS are damaged as a result of a mutation and thus their folding is damaged and they become infected and produce the accumulations that destroy the nerve cells. The goal of the researchers was to examine the cells' reaction to the accumulations, and to understand how they can be helped to prevent them.

To this end, the researchers examined the control of genetic expression in the cells through genome-wide sequencing, and discovered that those with the HTT protein responded to its accumulation by increasing the level of saffrons that are designed to deal with heatstroke (which also causes problems with protein folding). Spherons are a family of "chaperone" proteins that are responsible for the proper folding of proteins in cells and for identifying those with the wrong fold and sending them for degradation (breakdown). In the cells with the accumulations of the FUS protein, they discovered that the level of saffron actually decreased. Following this, they asked to know if the increase or decrease in the level of saffrons is targeted and adapted to the fight against accumulations. To this end, they performed a scan in which they expressed 70 different spherons (one spheron each time) in the same cells using genetic methods. Thus they discovered that only a few of them really help the cells to fight the misfolding of the proteins, and those that help with this change between the two diseases.

Prof. Shelgi: "For the first time, we identified in human cells the specific champorons required to fight the proteins that cause Huntington's and ALS. When we overexpressed them in the cells, the proteins folded properly and the aggregations were prevented. If we find a way to make them express these saffrons more, we may be able to prevent the deterioration of the diseases."

It was later found that the saffrons that prevented the accumulation of ALS did the opposite with HTT - that is, they accelerated its accumulation. These findings indicate that the same spherons, in different versions, lead to opposite results in Huntington's and ALS. From this it can be concluded that the folding problems that cause these diseases are very different and require a specific set of tools to combat them. "Our findings are a first step to define the fight against these diseases, to prevent the misfolding of the proteins that cause them. The next step is to understand how to get the cells to express more the specific saffrons they require", concludes Prof. Shelgi.

Life itself:

Prof. Reot Shelgi, 43, is married with two children (10 and XNUMX), and lives in Haifa ("By virtue of being a mother and a scientist, I don't have much free time for hobbies").

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