Authors:

Tyler Merrill

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About Paper:

Parkinson's disease (PD) is a common neurodegenerative disease classified by dopaminergic cell loss within the region of the brain that controls motor outputs, the substantia nigra (SN). In neurons, presynaptic protein aggregation is prevalent in PD and observed in aggregate deposits called Lewy bodies. Namely, proteins such as alpha-synuclein (aSyn) and synapsin1 are key players in presynaptic signaling pathways and contribute heavily to aggregated protein deposits in the cytoplasm. Though these aggregates have been observed in PD pathology, the pathway by which the aggregation occurs is not understood. One potential mechanism involves liquid-liquid phase separation (LLPS), a physical phenomenon in which proteins with long disordered regions (such as aSyn or synapsin1) can form condensates or droplets, similar to a drop of oil in water. Furthermore, synaptic vesicles (SVs) can also undergo LLPS to produce SV clusters in the presynaptic neuron, though the effect of these phase transitions on protein aggregation and dysfunction is still unknown. In this project, fluorescence lifetime imaging microscopy (FLIM) and fluorescence/Forster resonance energy transfer (FRET) are investigated as a means to image the effects of concentration and protein modifications (phosphorylation, mutation, etc.) on aSyn-synapsin1-SV interactions in live neurons. In addition, a molecular dynamics simulation using GROMACS to predict protein behavior is considered. A deeper understanding of the mechanism by which protein aggregation occurs could revolutionize the way neurodegenerative diseases are understood, diagnosed, and treated in the future. Keywords: Liquid Liquid Phase Separation; Parkinson's Disease; Protein Aggregation; Alpha-Synuclein; Fluorescence Imaging

Source:

Purdue University / 2024

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Co-authors:

Tyler Merrill