Contagious zombies
In neurodegenerative diseases, including Parkinson's disease, a certain group of neurons dies, leading to motor disorders and other symptoms. Scientists have been trying to figure out why these neurons die for a long time. But it turns out that they may even be alive.
Researchers from Rockefeller University have found that neurons affected by Parkinson's disease can shut down, but not die. The team found that these "turned off" neurons release chemicals that also turn off healthy neighboring neurons. This leads to the tremor and lethargy observed in patients with Parkinson's disease.
Aging dopamine neurons (red) cause local inflammation and attack the immune cells of the brain – microglia (green). Source: The Rockefeller University.
New drugs aimed at stopping the process of cell inactivation will help prevent the disease or slow its progression.
Signs of aging
There are quite a lot of switched-off, but living cells in the human body. They are part of the normal aging process and turn off when DNA is damaged during division. This helps prevent the uncontrolled growth of damaged cells and the appearance of tumors.
However, aging is usually not observed in the nerve cells of the brain, because unlike other cells in the body, neurons stop dividing after completion of formation. But researchers have found that dopamine neurons, which regulate motivation, memory and movement with the help of the chemical messenger dopamine, can nevertheless become old.
The researchers decided to study all the functions of the SATB1 protein associated with Parkinson's disease in dopamine-producing neurons, whose activity decreases during the disease. They transformed human stem cells into dopamine neurons in a Petri dish. The SATB1 gene was knocked out in part of the neurons.
It was found that neurons without the SATB1 protein secrete chemicals that cause inflammation and, eventually, aging of the surrounding neurons. The researchers also showed other abnormalities, including damaged mitochondria and enlarged cell nuclei. None of these disorders appeared in dopamine neurons with the preserved SATB1 gene, nor did they appear in a separate set of non-dopamine neurons without SATB1. This means that the aging mechanism is specific to dopamine neurons.
The group then investigated the chain of reactions that causes a decrease in SATB1 expression. They found that the SATB1 protein usually suppresses the gene that produces the protein p21, which promotes aging. In other words, SATB1 protects dopamine neurons from aging.
When the researchers reduced the amount of SATB1 protein in the midbrain of mice, they found the same signs of aging, including damaged mitochondria and high levels of p21. Brain tissue of patients with Parkinson's disease also showed elevated levels of p21, which once again confirms the results of laboratory studies.
Zombie Neurons
This work may explain one of the mysteries of Parkinson's disease: why dopamine levels decline long before dopamine neurons actually die. They don't die, but they stop functioning. These aging cells are like fantasy zombies: not alive, but not dead, they turn the surrounding cells into their own kind.
The study opens up new possibilities for the treatment of Parkinson's disease. There are several senolytic drugs that can remove aging cells. Researchers suggest that such drugs will help patients suffering from Parkinson's disease. Another possible way to combat this is the development of new drugs specifically targeting SATB1 or p21.
Article by M. Riessland et al. Loss of SATB1 Induces p21-Dependent Cellular Senescence in Post-mitotic Dopaminergic Neurons is published in the journal Cell Stem Cell.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of Rockefeller University: The pathway to Parkinson’s takes a surprising twist.