Differential neuronal susceptibility as an avenue toward disease-modifying therapy for Parkinson

Parkinson's disease (PD) is characterized by the loss of neurons, accumulation of a protein called alpha-synuclein (alpha-syn), and neuroinflammation occurring through microglia, which are immune cells in the brain. Traditionally, researchers have believed that the death of neurons in PD results from harmful mechanisms taking place in these dying cells. Yet, if this were the case, why do only specific neurons die in PD? We hypothesize that only distinct populations, and not all, neurons die in PD because of a complex signaling system between the neurons, alpha-syn, and microglia that leaves some neurons more susceptible to the disease than others. Furthermore, we think that fats on the brain cells, being crucial in the communication between neurons and microglia, trigger a biochemical 'eat-me' signal from the neural cells to the immune system. This would make fats critical in determining the susceptibility of neurons in PD. To test this hypothesis, we will study the brain regions of PD patients who had different degrees of neuronal loss, alpha-syn accumulation, and neuroinflammation. We predict that our results will shed light on why specific neurons are susceptible to PD. This information will open the door for the development of biomarkers and effective therapies.