Brain cells that produce the neurotransmitter dopamine are the most vulnerable to cell death in Parkinson’s disease (PD), but the reasons for this are not known. New techniques have revealed that not all dopaminergic neurons are the same in their molecular profile. We will use this new information to determine which neurons are lost in brain tissue from PD models and people who had PD. With this information, we will improve our understanding of how these neurons are different and identify processes we may be able to target pharmacologically to prevent cell death.
We predict that 1) subpopulations of dopaminergic neurons with higher expression of genes involved in mitochondrial function will be lost in models of PD, and 2) humans have a higher percentage of dopamine neurons with high expression of these genes.
With reference to a recently published database of gene markers, we will classify model and human dopaminergic neurons into different categories based on their gene expression and location within a part of the brain called the substantia nigra. Then, we will measure, in select populations of neurons, genes involved in the regulation of mitochondrial function. Once the cells with the highest gene expression are identified, we will determine whether these are selectively lost in tissue from models and patients.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
This work could provide biological evidence for the difference between the extent of neuronal cell death in models (~15-40%) and human PD patients (>80%) and indicate which markers should be used to evaluate cell death in models. Furthermore, information on the molecular identity of the vulnerable subpopulations of dopaminergic neurons could lead to the identification of novel pathways for pharmacological targeting.
Next Steps for Development:
One marker of a subpopulation of neurons is an ion channel. Ion channels are readily targetable by drugs, so experiments could be performed in rodent models to determine whether modulating the function of this channel is protective against cell dysfunction and death.