Research in Parkinson’s disease has largely focused on events that occur within neurons that are lost in disease. However far more abundant than neurons in the human brain are a type of cell called astrocytes, which are supportive cells to neurons but also play a key role in orchestrating the brain’s response to environmental stimuli such as infections or injury. When activated by such stimuli, the astrocyte then influences how neurons work and their survival: this relationship is important in understanding why neurons die in disease. In Parkinson’s disease, astrocytes and neurons are exposed to a highly specific stimulus, that is, clumps of misfolded alpha-synuclein protein.
Our study seeks to understand how misfolded protein switches astrocytes at a molecular level, and then in turn, how the altered astrocyte behavior affects neuronal function and survival.
This study uses human induced pluripotent stem cells, which allow us to generate different cell types that are represented in the human brain. We have generated and characterized human iPSC-derived astrocytes and neurons. We will apply the misfolded protein to the pure astrocytes and pure neurons separately, and then additionally test the effect of misfolded protein when the astrocytes and neurons are cultured together. We will utilize transcriptomics to understand the ‘switch’ that occurs in astrocytes due to misfolded alpha-synuclein, and we will use a range of imaging and electrophysiological tests to study how astrocyte behavior affects neurons.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Our preliminary work has suggested that astrocytes, once activated by alpha-synuclein become toxic to nerve cells. Understanding the way, or mechanism, by which astrocytes become toxic would provide a new strategy for treatment of Parkinson’s disease based on preventing the reactivity of the astrocytes and thereby protecting neurons.
Next Steps for Development:
A detailed molecular and functional map of astrocytes and astrocyte-neuron interactions will generate potential targets for therapy. In the next stage, such targets would need to be modified genetically or chemically to see if that prevents the change in the astrocyte, and the resulting effect on neuronal survival. Once validated, a target could then be taken forward for clinical development.