Role of glia in LRRK2 mediated dopaminergic neuron degeneration

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PROJECT SUMMARY Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons. Currently about one million people live with PD in the United States, and as the risk of developing PD increases with age and the population of the elderly is increasing, the number of people suffering from this disease is expected to grow in the future. Developing targeted treatments that slow or halt disease progression will not only improve patient quality of life, but would also reduce the vast economic burden on society. LRRK2 G2019S is the most common missense mutation found in PD, and several organisms, including Drosophila, have been used to model LRRK2-mediated neurodegeneration. LRRK2 G2019S alters neurite morphology in vitro, and by expressing LRRK2 G2019S in the dopaminergic neurons of flies, we have recently shown that it induces an age-dependent reduction of neurite length and branching in vivo, prior to overt neuronal loss. Recent advances in Parkinson's disease research have revealed that PD not only affects neurons, but also the function of glial cells, rendering them unable to fulfill their physiological role in maintaining tissue homeostasis and facilitating neuronal transmission. Investigating the precise role phagocytic glia and astrocytes play in neurite loss and neuronal death is key to fully understanding the mechanisms leading to neurodegeneration. In Aim 1 of this proposal I will examine whether glial function if altered in aging mutant LRRK2–expressing flies. In Aim 2 I will evaluate whether inhibiting glial function affects neurite loss, neuronal death, and motor function across age in LRRK2 G2019S flies, and whether LRRK2 G2019S in the glia leads to or exacerbates neurodegeneration. In Aim 3 I will examine if morphological changes in neurite architecture result in functional changes at the synapse, and whether this phenotype is sensitive to glial activity: I will evaluate the number of synapses across age in LRRK2 G2019S flies, and using a functional imaging approach determine if neurite loss translates into alterations in synaptic function. The proposed studies will examine the relationship between neurite morphology, synaptic function, and glial phagocytic activity, and offer mechanistic insight into the role of glia in pathology. The results will provide a foundation for future research into novel interventions against PD development and progression.