In a study led by Prof. Yehoshua Goldberg from the Hebrew University, it was found that the contraction of brain cells may explain the constipation symptom among Parkinson's patients. The important finding is expected to help in the future in the diagnosis of Parkinson's disease already in its early stages
Parkinson's disease is the second most common degenerative disease of the nervous system (after Alzheimer's disease), and affects approximately one percent of the adult population. This severe neurological disease is characterized by a gradual impairment of the body's ability to move, such as balance problems, muscle stiffness, slowness of movement and tremors. The onset of these motor symptoms is associated with the death of dopamine-producing cells in the brain. It is now known that people diagnosed with Parkinson's begin to suffer from non-motor symptoms many years before the diagnosis: sleep problems, anxiety and depression, chronic pain, and the earliest symptom of Parkinson's disease - severe constipation. However, today it is not possible to advance the diagnosis of the disease based on these symptoms due to the fact that these are not unique symptoms, but those that are common among the elderly, and are therefore not specific enough to indicate a process related to Parkinson's.
Understanding the physiological mechanism
What may bring closer the day when it will be possible to diagnose the disease earlier, is the understanding of the physiological mechanism that underlies the non-motor symptoms in the unique context of Parkinson's disease. If the mechanism is understood, it will be possible to define early physiological markers that can be discovered through a simple test (for example, at a family doctor). This was the aim of the researchers, Prof. Yehoshua Goldberg from the Department of Medical Neurobiology at the Hebrew University and Prof. Jochen Roeper from Goethe University in Frankfurt, in their groundbreaking study published in the journal Science Advances. It is known that one can find in the brains of Parkinson's patients "Levy bodies", microscopic accumulations of intracellular waste that the cell cannot get rid of. The interesting thing is that the clusters appear exactly in the areas that have a clear connection to the non-motor symptoms, and this many years before the disease is diagnosed. For example, one of the first areas where Lewy bodies appear is an area in the brain stem that has cells responsible for accelerating the activity of the digestive system. However, today it is not known if the presence of Levi's bodies in this area causes constipation, and if so, how? Most experts in the field believe that Lewy bodies kill these cells and as a result there is a slowdown of the digestive system and constipation. The problem with this explanation is that Lewy bodies do not necessarily kill the cells in the brain stem. The researchers wanted to test the assumption that the pathological process that causes the formation of Lewy bodies in Parkinson's disease changes the electrical activity pattern of the cells that speed up the digestive system without the cells dying, and to check whether these changes can still cause the digestive system to slow down and become constipated.
The main content of Lewy bodies is the protein alpha-synuclein. Accordingly, for the purpose of the experiment, the researchers used an artificial virus to inject alpha-synuclein into only those cells in the brain stem that control the activity of the digestive system in adult laboratory mice. As mentioned, it is known that these cells develop Lewy bodies in Parkinson's patients.
Shrinkage of brain stem cells
The researchers found that a few weeks after the protein began to be expressed in the marrow stem cells, these cells began to shrink. Because of a biophysical connection between the size of brain cells and their electrical activity, the contraction caused these cells to slow down their electrical activity. This slowing affected the ability of these cells to speed up digestion, therefore causing it to slow down and cause constipation. "To the best of our knowledge, this is the first time that a causal relationship has been demonstrated between physiological changes that the alpha-synuclein protein causes in any cells in the brain and any preliminary symptom of the disease," says Prof. Goldberg. "Even before cells are damaged by the pathology, they can give a sign that the pathology has begun." According to the researchers, a decrease in the electrical activity of these cells should be reflected in the measurement of the activity of the vagus nerve, through which the fibers pass from these cells to the digestive system.
The current study is a breakthrough in the study of Parkinson's disease and its diagnosis, and may significantly affect the lives of countless people. In Prof. Goldberg's estimation, the fact that the protein alpha-synuclein changes the electrical activity of these cells (without killing them) in a way that leaves its signals on daily physiological activity, may one day lead to the development of a simple physiological marker for the early detection of Parkinson's disease. "Imagine a situation where a 55-60 year old man comes to the doctor and complains of severe constipation. It is known that most cases of constipation in the third age are due to changes in the large intestine. However, the vagus nerve almost does not affect the large intestine, so if the doctor finds that the indicators of the activity of the large intestine are normal, but in a certain test they see damage to the vagus nerve activity, it is theoretically possible to see this as a sign indicating a degenerative process in the brain stem that may be related to Parkinson's" says Prof. Goldberg , although he qualifies his words and says that today this is only a hypothetical proposal.
In Prof. Goldberg's laboratory, in the coming years, they will also strive to understand the brain mechanism of the other symptoms that cause the disease, such as anxiety and depression, chronic pain, and sleep disorders. Prof. Goldberg is currently a member of a European consortium (and-pd.com) who investigates the damage to the brain networks that underlies the anxiety and depression suffered by Parkinson's patients, and collaborates with Prof. Alex Binstock from his department to investigate the source of chronic pain in Parkinson's. The advantage of an early diagnosis based on physiological and other markers for Parkinson's disease is that it will be possible to intervene and prevent or delay the degenerative process in Parkinson's patients. Today there is still no such intervention. This is the most important challenge of Parkinson's research.
Prof. Goldberg emphasizes that the work would not have been possible without the dedication of Dr. Wei-Hua Chiu, a postdoctoral fellow in the laboratory, and without the help of other researchers from the Faculty of Medicine at the Hebrew University: Prof. Menachem Hanani, Prof. Rami Yaka, Dr. Dani Ben-Zvi and Dr. Hadar Arihan-Zakai. The research was supported by Prof. Goldberg's ERC Consolidator grant and by a joint research grant of the Israeli-German GIF Foundation with Prof. Roper, in whose laboratory some of the experiments were performed.
for publication in the scientific journal
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