A new study undertaken at the University of Haifa and published in the prestigious journal NPJ Parkinson’s Disease (Synaptic dysfunction and extracellular matrix dysregulation in dopaminergic neurons from sporadic and E326K-GBA1 Parkinson’s disease patients) has for the first time found a connection between Parkinson’s disease and the extracellular matrix in the brain.
The study found evidence of changes in the genes that encode proteins of the extracellular matrix among Parkinson’s patients with a genetic background and those with a sporadic disease.
“To gain a deeper understanding of Parkinson’s disease and make progress in efforts to find a cure for the disease, we need to examine the changes that occur in the extracellular matrix,” explained the study’s author Prof. Shani Stern. “Until now, most of the studies concerning Parkinson’s have focused on the cells and synaptic connections. The results of our study found changes in the extracellular matrix, which has not been a focus of Parkinson’s research.”
Parkinson’s disease is caused by damage to cells in the Substantia nigra, an area of the brain that produces dopamine, a substance that is used to transfer messages between cells in the brain and plays a key role in our ability to perform normal motor functions.
According to Prof. Stern, one of the main problems in studying Parkinson’s disease is that only 15% of cases have a known genetic cause, while the remaining 85% are considered “sporadic.” Accordingly, it is only possible to create a model for the disease in animals in 15% of cases.
The current study was undertaken by Prof. Stern from the Sagol Department of Neurobiology in cooperation with the Salk Institute in San Diego, Erlangen University in Germany, and UCL in London.
The study used the reprogramming of cells into stem cells. Prof. Stern took skin cells from Parkinson’s patients, reprogrammed them into stem cells, and then differentiated them as cells of a different type (dopaminergic neurons) that carry the same genetic information as the person from whom they were taken.
In this case, the researchers used samples of skin cells taken from 10 patients. Some of these patients are suffering from Parkinson’s disease of genetic origin with the GBA1 gene mutation, which is associated with Gaucher’s disease.
Gaucher’s patients carry a mutation in two copies of the GBA1 gene; if a person has only one copy with mutation, they are at an elevated risk of developing Parkinson’s disease. The other patients in the study had sporadic Parkinson’s disease, with no known genetic changes or mutations.
“We know that mutations in the GBA1 gene are responsible for storage diseases such as Gaucher’s, and they are now also regarded as the commonest risk factor for Parkinson’s,” Prof. Stern noted.
The skin cells were “reprogrammed” as stem cells which were then differentiated into dopaminergic cells so that the cells carried the same genetic information for each participant in the study. The same process was also undertaken for healthy participants who served as a control group.
The extracellular matrix is part of the tissue that surrounds the cells and provides them with structural support. In addition to its structural function, the matrix also performs various other functions, such as separating different tissues and controlling communication between cells.
According to Prof. Stern, researchers have discovered in recent years that in addition to structural support, the extracellular matrix also fills various physiological functions and is involved in the creation and destruction of synapses (connections) between cells, the development of synapses, and synaptic plasticity. She adds that today the extracellular matrix is regarded as one of the four parts of the synapse: the presynaptic neuron, the postsynaptic neuron, the glial cells, and the extracellular matrix. Accordingly, the term “tetra-partite synapse” is now in common use.
The findings show evidence both among Parkinson’s patients with the GBA1 mutation and among patients with sporadic disease, of changes in the expression of numerous genes that encode proteins of the extracellular matrix.
For example, it was found that cells produced from Parkinson’s patients have less mRNA and fewer proteins that build the extracellular matrix than cells produced from healthy individuals. The researchers also discovered for the first time that the collagen 4 protein, which plays an important role in building the extracellular matrix, undergoes aggregation in Parkinson’s patients, but not in healthy individuals.
“The changes appear at the same time in the differentiation process, when we see a decline in the synaptic activity of the neurons created from Parkinson’s patients and a decline in their ability to transfer neural messages to other cells, and we therefore believe that there is a connection between the two processes” Prof. Stern explained.
