A new target for drugs against Parkinson's disease
Parkinson's disease causes degeneration of neural stem cells
LifeSciencesToday based on the materials of the Salk Institute for Biological Studies:
Scientists Pinpoint Key Player in Parkinson's Disease Neuron LossWhen reprogramming skin cells of patients with Parkinson's disease caused by one of the known genetic mutations, scientists at the Salk Institute for Biological Studies have identified damage to the membranes of the nuclei of brain stem cells, which, in their opinion, is a powerful factor in the development of this neurodegenerative disease.
The findings, published in the journal Nature (Liu et al., Progressive degeneration of human neural stem cells caused by pathogenic LRRK2), may help in the development of new methods for the diagnosis and treatment of Parkinson's disease.
American scientists have found that a mutation in the gene encoding the enzyme LRRK2 (leucine-rich repeat kinase 2), responsible for the development of both familial and sporadic cases of Parkinson's disease, causes deformation of the membrane surrounding the nucleus. A change in the architecture of the nucleus leads to the destruction of these important cells, as well as to a decrease in their ability to differentiate into functional neurons, including those responding to dopamine.
The results of laboratory studies were fully confirmed in the study of brain cells of patients with Parkinson's disease: the same damage to nuclear membranes was observed in autopsy samples.
"This discovery helps explain how Parkinson's disease, which is traditionally associated with the loss of dopamine–producing neurons and subsequent motor disorders, leads to motor dysfunction and other common non-motor manifestations of the disease, such as depression and anxiety," says Juan Carlos Izpisua Belmonte, professor at the Gene Expression Laboratory Of the Salk Institute, who headed the research group. "In the clinical trials currently underway, the possibility of compensating for dopamine deficiency with the help of neural stem cells is being studied. Our work provides a platform for similar trials using corrected cells of a particular patient. We consider the degeneration of the nucleus as a previously unknown factor in the development of Parkinson's disease."
Although, according to scientists, they do not yet know what these nuclear aberrations are – the cause of Parkinson's disease or its consequence – in their opinion, this discovery may be the key to new therapeutic approaches.
So, they managed to correct the LRRK2 mutation in the nucleus of the patient's stem cells using target gene editing techniques. Genetic correction restored the nuclear membrane, increased overall survival and enhanced the function of neural stem cells.
Damage to the nucleus was also avoided by chemical means, obtaining the same results as with genetic correction.
The diagram from the article in Nature shows the differences between a normal neural stem cell (left) and one carrying a mutation in the LRRK2 gene, including an increased level of apoptosis, a violation of the structure of the nuclear envelope, the ability to divide and the possibility of spontaneous differentiation into a mature neuron. These disorders can be suppressed with the help of an inhibitor of the corresponding enzyme or gene correction of a mutant gene.
"This opens up prospects for drug treatment of patients with Parkinson's disease caused by this mutation," Professor Belmonte believes.
In his opinion, the newly obtained data will help clinicians in the diagnosis of this form of the disease.
"The vivid manifestation of the deformation of the nuclei in the brain samples of patients allows us to add the parameters of this deformation to the list of diagnostic signs of Parkinson's disease," the scientist continues.
The research group, which included scientists from China, Spain, the University of California at San Diego (University of California, San Diego) and the Scripps Research Institute, made their discovery on human induced pluripotent stem cells (iPSCs). These cells are similar to natural stem cells, such as embryonic stem cells, except that they are derived from adult tissue cells. Obtaining iPSCs is associated with high expectations in the biomedical community due to the potential of these cells in the field of transplantation. In addition, they provide exceptional opportunities for scientific research.
"With these cells, we can model diseases in a way that cannot be done using traditional research methods, such as resistant cell lines, primary cultures and animal models," explains Belmonte.
In this study, scientists reprogrammed fibroblasts of patients with Parkinson's disease with a mutation in the LRRK2 gene into iPS cells, and then transformed iPSCs into neural stem cells.
Having modeled the aging process of these neural stem cells, the researchers came to the conclusion that in Parkinson's disease, old neural stem cells show more and more pronounced deformation of nuclear membranes and violation of the architecture of nuclei.
"This means that in time dynamics, the LRRK2 mutation negatively affects the nuclei of neural stem cells, preventing their survival and reducing the ability to differentiate into neurons," explains Professor Belmonte.
"As far as we know, we were the first to demonstrate that Parkinson's disease caused by aberrant LRRK2 affects human neural stem cells," the scientist continues. "Prior to the development of these reprogramming methods, research on human neural stem cells was very difficult, since they are isolated directly from the brain."
Professor Belmonte suggests that in this form of Parkinson's disease, pools of dysfunctional neural stem cells – the result of a mutation in the LRRK2 gene – may contribute to the development of other symptoms of the disease – depression, anxiety and inability to recognize odors.
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