Understanding the physiological and pathological relevance of liquid-liquid phase separation by synuclein family of proteins

ended

Proteins are among the most essential molecules of life. In recent times, it has been discovered that proteins can undergo liquid-liquid phase separation (LLPS) to form highly efficient droplet reservoirs for its functionality. However, these concentrated protein droplets can also lead to pathological protein aggregation and toxic amyloid fibril formation. One such example is α-synuclein (α-Syn), which can undergo LLPS-mediated amyloid aggregation associated with Parkinson’s disease (PD) pathogenesis. The physiological and pathological relevance of α-Syn LLPS remains elusive in the context of many biological factors such as familial mutations, presence of other synucleins, protein modifications and lipid membrane interaction. All of these factors significantly modulate the aggregation of monomeric α-Syn in solution. In this proposal, I aim to elucidate and quantify the effects of these mentioned in vivo relevant factors on the phase separation of α-Syn in a high throughput (HTP) and quantitative manner. While my work was the first to show that α-Syn can undergo LLPS; the host laboratory has developed a microfluidics based HTP method perfectly suited for protein LLPS related research. During the course of this project I will get trained on this particular technique along with several other sophisticated instruments. The outcome of this project will significantly help to elucidate the molecular origins of PD and provide important insights with respect to the onset time and progression of PD pathology, which is currently poorly understood. The knowledge obtained from this study will have crucial impact on the European society and the results might also be of interest to the pharmaceutical industries to effectively design new drugs against the progression of PD pathology in the long run.