Comprehensive coverage

A mechanism has been discovered that causes sleep apnea in sick children

One of the diseases resulting from such mutations in the PHOX2B gene is the disease CCHS. This is a rare and life-threatening syndrome in which babies, children and adults stop breathing as soon as they fall asleep. The patients must be connected to ventilators in order not to die in their sleep

Nerves. Credit: Mahmoud Ali-Saleh
Nerves. Credit: Mahmoud Ali-Saleh

Different genetic mutations cause a variety of neurological diseases. The common denominator between diseases caused by the elongation of the chains of the amino acid 'alanine', led scientists from Ben-Gurion University of the Negev and Tel Aviv University to investigate a rare and life-threatening condition related to a rare syndrome called CCHS, which causes apnea during sleep. The research findings were published in the prestigious journal EMBO Journal. The collaboration took place under the auspices of the Israeli CCHS patient organization 'Yad Lanshima'.

There are nine different neurological diseases, which are caused by genetic mutations in which there is a lengthening of the amino acid alanine chains in proteins that are expressed in the cell nucleus. The common denominator between the diseases motivated the Prof. Gad Vatin from the Faculty of Health Sciences at Ben-Gurion University of the Negev and you Dr. Avraham Ashkenazi from the Faculty of Medicine at Tel Aviv University To ask what is the role of those alanine sequences in health and disease.

One of the diseases resulting from such mutations in the PHOX2B gene is the disease CCHS. This is a rare and life-threatening syndrome in which babies, children and adults stop breathing as soon as they fall asleep. Therefore, CCHS patients must be connected to a ventilator as soon as they fall asleep, otherwise they will die of suffocation. In this situation, the autonomic nervous system, which is supposed to control involuntary bodily functions such as breathing, digestion and heart rate control, is damaged.

Prof. Gad and Tin from Ben-Gurion University in the Negev He is an expert in the study of rare diseases using induced stem cells that are adapted to the patient, whereas Dr. Avraham Ashkenazi from Tel Aviv University He is an expert in diseases in which there is a lengthening of amino acid sequences, and in the study of protein degradation pathways in the cell. Although both of them did not work on the same diseases, the 'Yad Lanshima' hospital organization saw fit to suggest that they collaborate to find treatments for the CCHS disease.

In Prof. Wetin's laboratory, they used a reprogramming technique, developed by the Japanese scientist who won the 2012 Nobel Prize in Physiology and Medicine, Shiniya Yamkanaka. This technique makes it possible to take relatively accessible cells (such as blood cells or skin cells) 'back in time' to a state identical to embryonic stem cells. These cells can differentiate into all types of cells present in the body, thus allowing access to human cells that are normally inaccessible for research, such as nerve cells. In this way they created stem cells from CCHS patients. The stem cells differentiated into cells of the autonomic nervous system simulating the disease state (disease-in-a-dish). With the help of Dr. Ashkenazi's expertise, the researchers discovered that in the disease there is an impairment of the function of the ubiquitin protein degradation system. The ubiquitin system was discovered by Prof. Aharon Chechenover, Prof. Avraham Hershko and Prof. Irwin Rose And for this discovery they were awarded the Nobel Prize in Chemistry in 2004. The research teams from the laboratories of Prof. Vatin and Dr. Ashkenazi demonstrated that a gene therapy approach that expressed a specific enzyme (UBA6) in the ubiquitin system was able to prevent damage to autonomic nerve cells from CCHS patients. 

The doctorates Fatma Amer-Zarzour From the laboratory of Dr. Ashkenazi andDaniel Falik From the laboratory of Prof. Vetin, who led the research, they discovered that the mutation that causes the lengthening of the alanine chain in the PHOX2B protein impairs the protein's ability to move into the cell nucleus. "We found that the ubiquitin system mistakenly binds to the mutation in PHOX2B outside the cell nucleus, and this causes the normal function of nerve cells to be inhibited," explained Falik and Amer-Zarzour. "This inhibition leads to the death of nerve cells in the autonomic system, and ultimately triggers the CCHS disease."

More of the topic in Hayadan:

Leave a Reply

Email will not be published. Required fields are marked *

This site uses Akismat to prevent spam messages. Click here to learn how your response data is processed.