Aggregation and inclusion body formation of heterogeneous nuclear ribonucleoproteins (hnRNPs) are linked to several neurodegenerative disorders. Recent advances reveal that these proteins undergo liquid-liquid phase separation (LLPS) to form droplets, a phenomenon that directly mirrors hnRNP function in RNA granule dynamic formation-dissolution. We postulate that pathologic RNP aggregation and their physiologic phase separation are intricately linked processes and manifested by the aging of RNP droplets. We propose to determine the molecular mechanisms of hnRNPA1 (a representative hnRNP family member) droplet maturation utilizing a combination of microscopy, fluorescence lifetime imaging and single- molecule spectroscopy techniques. Insights gained from this study will shed light on protein aggregation via LLPS, a hitherto unexplored protein aggregation pathway that is linked to multiple disease pathologies.
Heterogeneous nuclear ribonucleoproteins (hnRNPs) are key components of physiologic RNA granules and pathologic inclusion bodies. We propose to characterize how these two processes are linked using ultrasensitive fluorescence methods. Insights gained form the study will be invaluable in developing novel therapeutic strategies for aggregation-linked neurodegenerative disorders.
