Cortical Neuronal Vulnerability in Parkinson's Disease

Abstract Parkinson’s disease (PD) is a debilitating, progressive neurological disease characterized by accumulation of misfolded α-synuclein (referred to as Lewy pathology) that progresses throughout the brain and the loss of patient motor function. No disease modifying treatments are available, and therefore these patients continue to deteriorate throughout the disease. Therefore, this project intends to determine which neurons are vulnerable and resilient in PD, and what cellular dysfunction(s) they experience. This training intends to 1.) develop and refine skills in bioinformatics, genomics, and wet-lab techniques 2.) apply these developed skills to lead the independent research project outlined in this proposal 3.) enhance communication and presentation skills to ensure a successful transition to the next step in a career focused on neurodegenerative disease research. My previous work has determined that Lewy pathology bearing cells experience specific cellular dysfunctions which leads to activation of cell-death pathways. In addition, I have identified that specific neuron types are vulnerable (Layer 5 Intratelencephalic Neurons) and resilient (Layer 5 Pyramidal Tract Neurons) to Lewy pathology in the PD cortex. Expanding on my previous work, I will (Aim 1) identify resilient neurons and pathologic signatures in the PD cortex at single cell resolution using spatial transcriptomics. Through this, I will define the neuronal response to aggregates as they mature within individual neurons. Additionally, I will (Aim 2) determine the spatiotemporal basis of resilience to α-synuclein pathology. In this aim, I will determine whether disease stage (time) and/or symptom specific (brain region) treatments are targetable or determine if more universal disease modifying treatments are possible due to overlap in cellular dysfunctions across brain regions and time points. In addressing these two aims, we gain understanding of the stages of molecular response to Lewy pathology as aggregates mature, as disease progresses, and in multiple brain regions and therefore gain understanding of the mechanisms of resilience to Lewy pathology. In addition, we identify pathways and specific genes to target for disease modifying treatment of Parkinson’s disease. Finally, the proposed training goals and objectives provide an excellent foundation in the requisite skills and expertise necessary for a successful future career in neurodegenerative disease research.