Stem cells and neurodegenerative diseases (4)

Stem cells and Parkinson's disease

Continuation. The beginning of the article is here.

Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease, affecting almost 1% of elderly people worldwide. The main characteristic of the disease is the death of dopaminergic neurons of the nigrostriatal system and the compact part of the black matter of the brain. Another characteristic feature is the presence of Levi bodies (alpha-synuclein aggregates), which further aggravate the death of neurons as a result of a violation of the profile of nerve impulses. In cases of genetically determined familial Parkinson's disease, the involvement of ubiquitin-carboxyconc hydrolase L1, serine-threonine kinase 1, parkin enzyme, DJ-1 deglycase, alpha-synuclein and leucine-rich repeat kinase-2 was revealed. Environmental factors, combined with age, genetic polymorphisms and exposure to chemical compounds, can cause a person to develop sporadic Parkinson's disease, but its complex etiology has not yet been fully studied. Fitzmaurice et al. It was found that variations of the enzyme aldehyde dehydrogenase enhance the effect of pesticides associated with Parkinson's disease, which demonstrates the interaction between environmental factors and genetic characteristics.

Muscle tension-induced numbness, resting tremor and bradykinesia are the main symptoms that make Parkinson's disease the most common mobility disorder affecting people over the age of 65. Mechanistic and pathophysiological studies have allowed us to look far into the depths of the disease. Parkinson's disease is usually associated with a violation of calcium homeostasis, inflammation, violation of kinase-mediated signaling pathways, formation of reactive oxygen species and mitochondrial dysfunction. Animal and cellular models have made it possible to understand in detail the mechanisms of the disease, but the data obtained are not always applicable to humans due to differences in the pathogenesis of the disease in humans and animals.

To date, monoamine oxidase inhibitors, dopamine agonists, levodopa and deep stimulation of brain tissues are used in Parkinson's disease. The latter approach involves stimulation of the ventrolateral nucleus of the thalamus, which significantly reduces the severity of tremor. Other symptoms, such as numbness and bradykinesia, can also be relieved by stimulating the subthalamic nucleus or the inner segment of the pale globe. However, these methods do not provide recovery of damaged regions of the brain, and oral medications lose their effectiveness 5 years after the start of administration. The use of L-dopa (levodopa, L-dihydroxyphenylalanine) can cause dyskinesia and does not slow down the progression of the disease.

The earliest transplant studies used fetal ventral mesencephalic tissue of human origin, which was implanted into the striatum of patients with Parkinson's disease. These attempts were successful, and in successful cases, symptomatic improvement persisted for almost 16 years. However, the success of this approach was overshadowed by the likelihood of adverse side effects, such as graft-induced dyskinesia. The reason for their development was the presence of serotonergic neuroblasts in the transplanted tissue, which led to a violation of the ratio between serotonin and dopamine carriers and an unbalanced release of dopamine. Studies have also shown that the survival rate of transplanted fetal mesenchymal cells is very low, and ethical issues have made it even more difficult to implement this therapy. Since Parkinson's disease is characterized by the regional death of dopaminergic neurons, transplantation (restoring the cell population) therapy using stem cells and iPSC-derived dopaminergic neurons (providing a clean population) injected into the area of the substantia nigra is a promising alternative.

Neurons with a dopaminergic phenotype are obtained from embryonic stem cells using the sonic hedgehog protein (Shh) and fibroblast growth factor-8, or from genetically modified neural stem cells by overexpression of Nurr1. Previously, dopaminergic neurons were successfully obtained by the joint cultivation of stromal stem cells of the bone marrow of mice and monkey embryonic stem cells. Further studies have demonstrated successful intrastrial (inside the striatum) transplantation of human neural stem cells of the fetal brain to monkeys with simulated brain damage, which provided an improvement in behavioral changes. Another study described that nerve stem cells isolated from the patient's brain, converted into dopaminergic neurons and implanted back into the patient's brain significantly reduced the severity of symptoms such as trembling and numbness. The results of brain scans showed an increase in dopamine production by almost 58%, while even in the absence of a further increase in dopamine levels, symptoms did not return, which indicates a possible recovery potential of dopaminergic neurons derived from stem cells.

The transition from pluripotent stem cells to iPSCs has demonstrated promising results and opened up new prospects for modeling Parkinson's disease. Dopaminergic neurons obtained from iPSCs were successfully transplanted into the striatum of a rat model of Parkinson's disease, which provided a significant reduction in the severity of motor asymmetry. An important role in the development of Parkinson's disease is assigned to mitophagy. The mitochondrial-specific PINK1 kinase accumulates in the outer mitochondrial membrane during repolarization, activating the parkin protein, which in turn initiates mitophagy. The data obtained in animal models have already generated controversy about the involvement of mitophagy in the development of Parkinson's disease. However, dopaminergic neurons with PINK1 gene mutations obtained from the patient's iPSCs allowed researchers to develop a clearer vision of the theory of mitophagy, which once again confirms the pronounced advantage of stem cell models of human diseases over any animal model. There is also an opinion that mitophagy may be the result of aging and not have a direct correlation with the disease, but this hypothesis has not been confirmed to date. Progerin expression and long-term cultivation were used for artificial aging of neurons in culture. Such aged neurons were used as a model to study the late onset of Parkinson's disease and decipher the phenotypes of the disease.

As mentioned earlier, in addition to disease modeling, stem cells and iPSCs have great potential as a tool for in-vitro screening of therapeutic agents, drugs and compounds. There is evidence that rapamycin, GW5074 (LRRK2 kinase inhibitor) and coenzyme Q10 reduce the severity of cytotoxic effects of concanamycin A, also known as valinomycin, on neurons obtained from iPSC patients. It was clearly shown that GW5074 does not suppress oxidative stress in healthy neurons of the control group, while effectively suppressing it in neurons derived from patients' cells carrying the PINK1 mutation. This difference underscores the importance of screening therapeutic compounds on cells carrying mutations of diseases, as well as on cells of healthy people. Another example of the use of stem cells in the study of the physiology of Parkinson's disease is the correction of the A53T mutation in the alpha-synuclein gene using the genome editing method, suppressing the formation of Levi bodies in dopaminergic neurons obtained by their iPSCs. Thus, iPSCs carrying mutations are an excellent tool for screening and assessing the biosafety of drugs and compounds, as well as for identifying the underlying signaling cascades and new therapeutic targets. Obtaining and identifying iPSCs is a very complex process, and a differentiated population of dopaminergic neurons may contain traces of undifferentiated cells, which can lead to the formation of a teratoma. Therefore, the direct conversion of the patient's fibroblasts into dopaminergic neurons would allow overcoming the limitations associated with iPSC. Successful differentiation of fibroblasts into dopaminergic neurons is described in the literature and can be used to model diseases. Stem cell technology can be used to identify biochemical markers of the disease, which will help in the diagnosis of early forms of Parkinson's disease.

Continuation: Stem cells and amyotrophic lateral sclerosis

Portal "Eternal youth" http://vechnayamolodost.ru  01.03.2017