Investigating the role of glial pruning in Parkinson's Disease.

Abstract

Parkinson’s Disease (PD) is the second most common and fasting growing neurodegenerative disease.PD is characterized by the loss of dopaminergic neurons in the substantia nigra of the brain leading to several motor phenotypes, including bradykinesia, rigidity, and resting tremors. However, nonmotor symptoms and neuron loss in other areas of the brain are seen even before disease diagnosis. Several genetic and environmental risk factor exposures even earlier in life may predispose an individual to develop PD. The gene PRKN/PARK2 is one of these genetic risk factors that causes an early-onset autosomal recessive PD. Much of the research on this gene focuses on its role in neurons despite its broad expression in other cells, including glia. In this thesis, I identify the role of pdr-1/PRKN/PARK2 in glial engulfment of neuron receptive endings using the AFD neuron – AMsh glia pair in C. elegans. Using this model, I demonstrate that pdr-1/PRKN acts downstream of neuron activity to regulate engulfment via the JNK pathway and the GTPase ced-10/RAC1. This function of pdr-1/PRKN acts in the AMsh glia through its ligase-independent short isoform. This isoform regulates engulfment during a critical developmental window and loss of pdr-1/PRKN affects AFD neuron shape only in aged animals. Finally, I identify specific variants in genes associated with engulfment are enriched in individuals with PD. Together, this dissertation provides evidence for the role of glial engulfment in PD disease development.