Synaptic Paths to Neurodegeneration: The Emerging Role of TDP-43 and FUS in Synaptic Functions

Figure 3

Assembly principle for RNP granules. (a) RNA-binding proteins typically can be separated into RNA-binding domains and low-complexity prion-like domains. Low-complexity domains are intrinsically disordered and can form multivalent weak interactions which nucleate to form phase separation. Posttranslational modifications (PTMs) could aid the occurrence of phase transition. Phase separation generates a phase boundary, such as RNP granules. RNP granules mature into a hydrogel-like state where the molecules have reduced movement. The enrichment of aggregation-prone proteins within the RNP granules may result in the formation of irreversible aggregations observed in neurodegenerative diseases. (b) In neurons, there are three main types of RNA granules: transporting granules, stress granules, and processing body (P-body). Each of them is proposed to perform different functions. Each type of granule can present stereotypical markers but also share common components. Based on the liquid-liquid demixing, the components can easily transition from one type of granule to another as part of the RNP granule continuum.