Super-Resolution In Vivo Optical Imaging as a Window to Parkinson's Disease Pathogenesis

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Parkinson's disease is a debilitating neurodegenerative disorder afflicting 5 million people worldwide, costing $14 billion a year in the United States alone. The causes of most cases are unknown, but genetic and environmental factors are linked to increased risk. This project will reveal the molecular events related to Parkinson's disease neuropathology and progression, thus facilitating new therapeutic interventions and more accurate prognoses. More generally, a tool will be developed for identifying the molecular basis of other central nervous system disorders related to protein folding, such as Alzheimer's disease and amyotrophic lateral sclerosis, and for evaluating new treatment methods for these diseases. Undergraduate students will be incorporated into aspects of this project with graduate students. The research will be used to enhance demonstrations for the Purdue Women in Engineering program and at the Brain Bowl during Purdue's Spring Fest, both of which target K-12. The laboratories involved on this project will be opened to students in classes that the investigators teach to illustrate concepts and demonstrate the relevance of class material to research, an exciting tool for encouraging graduate research and education.A new fluorescence-based optical molecular imaging method suitable for the living brain will be developed and applied as a means to elucidate, for the first time, pathogenic mechanisms relating to the temporal and spatial development of Parkinson's disease neuropathology. Abnormal protein aggregation of the presynaptic protein alpha-synuclein is thought to be a critical early pathogenic event, and aggregation is postulated to occur first systemically, then in the brain stem, and then in later stages in specific areas of the brain where neuronal loss or dysfunction results in the cardinal motor and non-motor symptoms. The spread of aggregates through these different brain regions is thought to be similar to the spread of the prion protein involved in mad cow disease and Creutzfeldt-Jakob syndrome. Understanding the relationship between alpha-synuclein aggregation and Parkinson's disease is of fundamental importance, in order to develop detection and treatment options. Aberrant calcium signaling is also a key Parkinson's disease indicator, and calcium ion perturbations in vulnerable neurons can be monitored with available fluorescent reporters. The proposed super-resolution optical imaging method will have the capacity to determine alpha-synuclein aggregation and site progression as well as calcium signaling in the brain of a living animal, potentially with a resolution of ten microns. The Research Plan is organized under two aims. Under the FIRST Aim, a simultaneous computational imaging and rat model study will be pursued to investigate the alpha-synuclein prion-like spreading mechanism that is thought to result in Parkinson's disease progression. Data collected weekly will be progressively used to aid the determination of precise point locations for alpha-synuclein aggregation. The fluorescent lifetime distribution of these sites is also expected to differ, based on aggregation level. Under the SECOND Aim, temporal signaling information will be obtained from microscope measurements of fluorescent calcium reporters in cell cultures and used to simulate neuron activation in the brain. This joint experimental and modeling effort will build a framework to allow investigation of whether perturbations of calcium signaling underlie neuron dysfunction or loss in Parkinson's disease, and the hypothesis that interactions between calcium and alpha-synuclein are involved in neurotoxicity.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.