FIGURE 2.

Phase-separated membraneless organelles have distinct components and functions. Schematic of membraneless organelles implicated in TDP-43 and/or FUS biology. Neurons contain nucleoli, which are condensed regions associated with ribosomal RNA synthesis. TDP-43 and FUS have been observed to localize to the nucleolus, which is commonly marked by fibrillarin and rRNA (see Nucleoli). Cajal bodies (CBs) are closely associated with nucleoli and commonly found in neurons. Major CB markers include coilin and the presence of small Cajal body-specific RNA (scaRNA). While not demonstrated to colocalize, TDP-43 is implicated in CB formation and regulation (see Cajal Bodies). Another nuclear membraneless organelle relevant to TDP-43 and FUS biology includes paraspeckles (see Paraspeckles). The long non-coding RNA (lncRNA) NEAT1 is an integral RNA component of paraspeckle organization, and these condensates are commonly marked by NONO. TDP-43 has been demonstrated to be important regulator of paraspeckle formation and it is shown to localize to the shell of paraspeckles, whereas FUS is generally localized to the core (West et al., 2016). Cytoplasmic stress granules are recently implicated in neurodegenerative diseases, and G3BP1 has been demonstrated as a central protein involved in SG formation (Yang et al., 2020). Stress granules stall protein translation and mRNA is a common RNA component of these condensates. Both TDP-43 and FUS demonstrate SG recruitment in neurons (see Stress Response). A final membraneless organelle covered in this review includes transport granules. These granules are observed in dendrites and axons of neurons. TDP-43 and FUS are both implicated in their formation, and these condensates often include mRNA, which is shuttled away from the soma for local translation (see Transport Granules and Local Translation). Created with BioRender.com.