A new study at the University of Haifa published in the prestigious journal NJP Parkinson’s Disease (Reduced synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons from Parkinson’s disease patients) has identified for the first time neural processes that are common to different types of the disease.
The processes are related to the ability of cells to connect to the extracellular matrix and their capacity to create new synapses. Thanks to the use of the innovative Sendai Reprogramming technique, the researchers were able to show for the first time that even in sporadic Parkinson’s patients for which no animal model has yet been developed, these processes are also impaired.
“Most of the current studies were undertaken on a small number of familiar Parkinson’s mutations caused by genetic factors since it is not possible to create models for sporadic forms of the disease. Thanks to the ability to create induced pluripotent stem cells for patients with “sporadic” disease, we managed to show for the first time the presence of impaired neural and cellular mechanisms in a similar manner across all the types of disease we examined,” explained Dr. Shani Stern, the corresponding author of the study.
Parkinson’s patients suffer from massive loss of nerve cells in the area of the brain known as the Substantia nigra, which is packed with dopaminergic neurons. Dopamine is required in the process of transfer of messages between brain cells and plays a key role in our ability to perform motor actions properly. One of the problems in the research and development of drugs is the fact that only 15 percent of Parkinson’s cases are caused by known genetic factors, while 85 percent are defined as “sporadic.” Accordingly, it is only possible to create a model for the disease in animals relating to those 15 percent of the cases.
In recent years, however, a method has been developed based on the “reprogramming of mature cells into induced pluripotent stem cells.” According to this method, which was used in the current study, the researchers take cells from specific individuals, reprogram them into stem cells, and then differentiate them as cells of a different type carrying the same genetic load as the individual from whom they were taken.
In the current instance, Dr. Stern from the Sagol Department of Neurobiology at the University of Haifa (in cooperation with Prof. Fred Gage from the Salk Institute; Prof. Alexis Brice from ICM, Paris; Prof. Juergen Winkler from FAU, Germany; and Prof. Irit Sagi from the Weizmann Institute) worked on skin cell samples taken from nine patients suffering from Parkinson’s disease. Some of the patients were diagnosed with genetic mutations while others had the “sporadic” disease. The skin cells were “restored” to stem cells, which the researchers then differentiated inot dopaminergic neurons so that the cells carried the genetic load of each specific patient and were effectively “sick” with the same type of Parkinson’s disease as that participant. The process was also used for four healthy participants constituting a control group.
In the second stage, the researchers sequenced the RNA expressed in the dopaminergic cells and prepared an electrophysiological profile of the cells, measuring electric currents and potentials in the nerve cells. The RNA sequencing enabled the researchers to understand which genes were expressed at a high level and which were less expressed relative to the control group. Dr. Stern used bioinformatical techniques to analyze the results of the RNA expression, revealing some pathways where the rate of expression in the patients was elevated and others where it was suppressed.
The findings showed that both the patients with a genetic disease and those with a sporadic disease showed a decline in the ability of the cells to bond with the extracellular matrix through focal adhesion. The extracellular matrix is the structure between the cells that contributes to cell stability, proper development, and the ability to create synapses (connections) between cells. “We know that once cells do not bond properly to the matrix, a special cell suicide mechanism called anoikis is activated,” Dr. Stern explained.
The study found additional evidence of possible damage to the structures of the extracellular matrix – a decline in the quantity of the proteins that build the matrix, likely leading to the emergence of an unstable structure that in turn causes instability, disconnection, and death in the cells. The researchers also found a decline in the synaptic activity responsible for the transmission of neural messages to the target cells among all the Parkinson’s patients in the study. “It seems that one of the results of the decline in matrix proteins is a decline in synaptic activity and in the ability of the cells to create functional synapses,” Dr. Stern noted.
“The dopaminergic neurons we examined were derived from patients through reprogramming which rejuvenates them into young cells. In other words, we can see changes in the electric activity, genes, and proteins of the extracellular matrix even when the cells are young. This implies that these changes exist in Parkinson’s patients long before they are aware of a disease process that is occurring in their brains. If we perform this sequencing in a young person and find a similar picture to that found among people who have developed Parkinson’s disease, we can assume that this individual will develop the disease at a later stage. Currently, most of the treatments are intended to prevent the exacerbation of the disease rather than to prevent it. If we can identify the potential to develop Parkinson’s disease at an early stage and develop treatments that can halt the advancement of the disease, we will be able to start preventative treatment at a stage when nerve cell mortality is limited. This will allow us to significantly slow down the progression of the disease,” Dr. Stern concluded.