Breakthrough in identifying common neural processes in Parkinson’s disease

New research could lead to treatments that halt the advance of Parkinson’s disease. Study from University of Haifa could have significant implications for how Parkinson’s disease is treated following a breakthrough in identifying common neural processes for the first time.

A new study conducted by University of Haifa has identified processes that may help prevent the spread of Parkinson’s disease. The study, published in NJP Parkinson’s Disease, has for the first time identified neural processes that are common to various different types of the disease. 

The processes relate to the ability of cells to connect to the extracellular matrix and their capacity to create new synopses. 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 patients for which no animal model has yet been developed, these processes are also impaired. 

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 the 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.

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.

Study author Dr. Shani Stern, a senior lecturer at the University’s Sagol Department of Neurobiology.

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, reprogramme them into stem cells, and then differentiate them as cells of a different type carrying the same genetic load of the individual from whom they were taken.

In the current instance, Dr. Stern along 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 into 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 study found additional evidence of a possible damage to the structures of the extracellular matrix – a decline in the quantity of the proteins that build the matrix – in both the genetic and sporadic form of the disease. It likely leads 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 the 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 brain. 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. 

Dr Stern

“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 the nerve cell mortality is limited. This will allow us to significantly slow down the progression of the disease,” Dr. Stern concluded.