RNA Granules and Diseases: A Case Study of Stress Granules in ALS and FTLD

Abstract

RNA granules are microscopically visible cellular structures that aggregate by protein-protein and protein-RNA interactions. Using stress granules as an example, we discuss the principles of RNA granule formation, which rely on the multivalency of RNA and multi-domain proteins as well as low-affinity interactions between proteins with prion-like/low-complexity domains (e.g. FUS and TDP-43). We then explore how dysregulation of RNA granule formation is linked to neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), and discuss possible strategies for therapeutic intervention.

Keywords: Low-complexity region; Phase separation; Prion-like domain; RNA granules; Stress granules.

Figure 1. Classes of SG components

(A) The defining first class of SG components includes subcomponents of the 48S pre-initiation complex, along with stalled mRNA transcripts. (B) A second class of proteins that either bind mRNA directly or are partners of RBPs. Many of these proteins contain unstructured domains and can nucleate SG assembly. Some are commonly used as “markers” to detect SGs by immunofluorescence (yellow flags). (C) Tertiary “piggy back” proteins, many of which function in cell signaling pathways (red arrows).

Figure 2. Schematic representation of the functional domains of TDP-43

TDP-43 is a 414-amino acid RBP with functions in transcriptional repression, splicing, and translational regulation. The vast majority of ALS-associated mutations occur within the C-terminal glycine rich PrLD. Table only includes data on studied links between ALS mutations and SG association in cellular models. Mutations are marked by red arrows and letters corresponding to table entries. NLS = Nuclear localization signal; RRM = RNA recognition motif; NES = Nuclear export signal; Tan shading = PrLD.

Figure 3. Schematic representation of the functional domains of FUS

FUS is a 526-amino acid RBP with functions in transcriptional repression, DNA damage repair, and splicing. The majority of ALS-linked FUS mutations occur within its NLS, linking its mislocalization to neurodegenerative pathogenesis. Table only includes data on studied links between ALS mutations and SG association in cellular models. Mutations are marked by red arrows and letters corresponding to table entries. NLS = Nuclear localization signal; RRM = RNA recognition motif; ZnF = Zinc finger domain; RGG = Arginine-Glycine-Glycine-rich domain; Tan shading = PrLD.