Sechenov Scientists Have Described Ways to Use Genetic Engineering to Treat Parkinson’s Disease

Parkinson's disease

Researchers at Sechenovskiy University, together with colleagues from the University of Pittsburgh, described the most promising areas of using genetic engineering in the study and treatment of Parkinson’s disease. Using this method, one can evaluate the role of various cellular processes in the development of the disease, develop new drugs and methods of therapy, the effectiveness of which can be further verified using animal models of Parkinson’s disease. Read more about the work in the journal Free Radical Biology and Medicine. 

Parkinson’s disease is a chronic neurodegenerative disease that leads to motor, cognitive impairment, and speech problems. Most often, the disease develops in older people (over 55-60 years old) and gradually progresses; in the later stages, a person cannot move and take care of himself. So far, no medication or method of therapy has been found that can restore the lost functions of the body, but it is possible to slow down the development and alleviate the symptoms of the disease with the help of medications and surgical operations. 

It is known that the onset of Parkinson’s disease is associated with a significant (50-70%) decrease in the number of dopaminergic neurons in the brain – nerve cells that transmit signals using the dopamine neurotransmitter. Another symptom is the appearance of Levi bodies in nerve cells – clusters of α-synuclein protein oligomers. 

Scientists have discovered quite a few mechanisms that may trigger or exacerbate the development of Parkinson’s disease. In approximately 10% of cases, the disease is hereditary, in other cases, the development of the disease is caused by both a genetic predisposition and environmental factors: the use of certain drugs, poisoning with pesticides or herbicides. 

The authors of the article focused on the possible causes of the disease, which are associated with redox reactions in cells and the mechanisms of programmed cell death – apoptosis and ferroptosis. Scientists considered these processes in the context of using CRISPR / Cas9 – one of the methods of genomic editing, which allows for various manipulations with DNA (for example, to add and cut individual nucleotide sequences in a molecule). 

“Parkinson’s disease is the second most common neurodegenerative disease in the world, the risk of developing which increases significantly with age. The disease affects the quality of life of patients, requires significant expenditures on medicines and care for such patients. CRISPR is a promising technology, strategy for the treatment and treatment of neurodegenerative diseases. The research potential of the technology is extremely large: you can turn off / start any genes, look at what processes they are involved in, track entire metabolic pathways, coming to an understanding of the origins of the disease, the mechanisms and pathways that need to be influenced. Particularly noteworthy is the use of CRISPR-editing to create animals and cell models that fully and accurately reflect the clinical picture of the disease, 

The first group of mechanisms that scientists have considered is related to the role of mitochondria in the development of the disease. In addition to supplying the cell with energy, mitochondria provide the synthesis of reactive oxygen species (ROS), which serve to transmit signals within the cell. Disruption of work or damage to mitochondria can lead to accumulation of ROS, which is dangerous for the cell, therefore, to maintain the integrity of the cell, it is necessary to remove damaged mitochondria in a timely manner, which the cell itself can perform (this process is called mitophagy). Ineffective or excessive mitophagy can cause damage to cells and tissues, including neurons. Studies also show that mutations in the genes encoding the PINK1 and Parkin proteins (they are involved in the regulation of mitophagy) are associated with the loss of dopaminergic neurons and muscle dystrophy characteristic of Parkinson’s disease. The work of several scientific groups suggests that the role of these proteins can be much more complicated and many other mechanisms may be involved in regulating the process of mitophagy, so it is too early to apply genome editing to influence their synthesis. Several other proteins and lipids are known to affect mitochondrial function and mitophagy (e.g. DJ-1, α-synucleins, Fbxo7 and cardiolipins), and CRISPR / Cas9 can be used to search for new genes and proteins associated with the disease and evaluate their role in development and progression of pathology. In addition, obtaining animals and cell models with various combinations of mutations will determine the role of these proteins in the development of the disease, as well as create experimental models that most accurately reflect the main features of the disease. that the role of these proteins can be much more complicated and many other mechanisms may be involved in the regulation of mitophagy, therefore it is too early to apply genome editing to influence their synthesis. Several more proteins and lipids are known that affect mitochondrial and mitophagic functioning (e.g. DJ-1, α-synucleins, Fbxo7 and cardiolipins), and CRISPR / Cas9 can be used to search for new genes and proteins associated with the disease and evaluate their role in development and progression of pathology. In addition, obtaining animals and cell models with various combinations of mutations will determine the role of these proteins in the development of the disease, as well as create experimental models that most accurately reflect the main features of the disease. that the role of these proteins can be much more complicated and many other mechanisms may be involved in the regulation of mitophagy, therefore it is too early to apply genome editing to influence their synthesis. Several more proteins and lipids are known that affect mitochondrial and mitophagic functioning (e.g. DJ-1, α-synucleins, Fbxo7 and cardiolipins), and CRISPR / Cas9 can be used to search for new genes and proteins associated with the disease and evaluate their role in development and progression of pathology. In addition, obtaining animals and cell models with various combinations of mutations will determine the role of these proteins in the development of the disease, as well as create experimental models that most accurately reflect the main features of the disease. therefore, it is too early to apply genome editing to influence their synthesis. Several more proteins and lipids are known that affect mitochondrial and mitophagic functioning (e.g. DJ-1, α-synucleins, Fbxo7 and cardiolipins), and CRISPR / Cas9 can be used to search for new genes and proteins associated with the disease and evaluate their role in development and progression of pathology. In addition, obtaining animals and cell models with various combinations of mutations will determine the role of these proteins in the development of the disease, as well as create experimental models that most accurately reflect the main features of the disease. therefore, it is too early to apply genome editing to influence their synthesis. Several more proteins and lipids are known that affect mitochondrial and mitophagic functioning (e.g. DJ-1, α-synucleins, Fbxo7 and cardiolipins), and CRISPR / Cas9 can be used to search for new genes and proteins associated with the disease and evaluate their role in development and progression of pathology. In addition, obtaining animals and cell models with various combinations of mutations will determine the role of these proteins in the development of the disease, as well as create experimental models that most accurately reflect the main features of the disease. and CRISPR / Cas9 can be used to search for new genes and proteins associated with the disease, and evaluate their role in the development and progression of pathology. In addition, obtaining animals and cell models with various combinations of mutations will determine the role of these proteins in the development of the disease, as well as create experimental models that most accurately reflect the main features of the disease. and CRISPR / Cas9 can be used to search for new genes and proteins associated with the disease, and evaluate their role in the development and progression of pathology. In addition, obtaining animals and cell models with various combinations of mutations will determine the role of these proteins in the development of the disease, as well as create experimental models that most accurately reflect the main features of the disease. 

The second group of cellular processes is associated with the accumulation of iron. For the cell to work, maintaining a certain level of iron and reactive oxygen species is very important, and this balance is disturbed in many neurological disorders. In animals and elderly people, iron accumulates in the brain tissues, especially in the areas responsible for motor and cognitive functions, apparently this is due to metabolic disorders in general. It was established that the accumulation of iron in one of these areas (black substance) leads to the death of dopaminergic neurons. In addition, the interaction of dopamine with iron can form toxic compounds that damage mitochondria and provoke clusters of α-synuclein oligomers in neurons. Scientists also study proteins that are involved in the transport of iron into neurons and its removal from cells: tau protein, transferrin, transferrin receptor, ferroportin, amyloid beta precursor. CRISPR / Cas9 can help in the search and synthesis of new drugs that effectively and accurately regulate the metabolism of iron in cells. This technology will facilitate the selection of treatment strategies for each individual patient. 

The third group of mechanisms studied by the authors of the article is related to the processes of programmed cell death, apoptosis, and ferroptosis. Apoptosis serves as a backup mechanism in case the destruction of damaged mitochondria is not enough to continue normal cell function. During cell death of this type, special enzymes destroy the proteins and DNA of the cell, and it is divided into fragments. Ferroptosis develops when lipid oxidation products accumulate in cells, in which iron plays an important role. Both types of cell death are involved in the development of neurological diseases, increasing the rate of death of dopaminergic neurons. Here CRISPR / Cas9 is useful both in detailed studies of the mechanisms of cell death and in the regulation of protein synthesis that contribute to or inhibit cell death. 

A functional analysis of the genome and synthesized proteins, with the help of which many of these results were obtained, has already shown its effectiveness in studies of schizophrenia, bipolar disorder, and autism spectrum disorders. In combination with CRISPR / Cas9, it will help to formulate the ideas of scientists about the genetic basis of Parkinson’s disease, accelerate the creation of individual cell models, the development of drugs and methods of therapy. 

“CRISPR technology has taken a huge step towards the use of genomic editing for the treatment of patients with severe diseases, which include neurodegenerative diseases. It has already been tested in a clinic (in China, USA, Germany), however, so far only for the treatment of patients with advanced cancer and β-thalassemia. Such studies will allow one to see the vast potential and possibilities of genomic editing as a method of treatment and therapy. It’s difficult not to experience a deep sense of excitement and trepidation, understanding that the development of genomic editing technologies can completely change our understanding of the treatment of Parkinson’s disease and other neurodegenerative diseases, ”Margarita Artyukhova added.