Stress granule subtypes: an emerging link to neurodegeneration

Abstract

Stress Granules (SGs) are membraneless cytoplasmic RNA granules, which contain translationally stalled mRNAs, associated translation initiation factors and multiple RNA-binding proteins (RBPs). They are formed in response to various stresses and contribute to reprogramming of cellular metabolism to aid cell survival. Because of their cytoprotective nature, association with translation regulation and cell signaling, SGs are an essential component of the integrated stress response pathway, a complex adaptive program central to stress management. Recent advances in SG biology unambiguously demonstrate that SGs are heterogeneous in their RNA and protein content leading to the idea that various SG subtypes exist. These SG variants are formed in cell type- and stress-specific manners and differ in their composition, dynamics of assembly and disassembly, and contribution to cell viability. As aberrant SG dynamics contribute to the formation of pathological persistent SGs that are implicated in neurodegenerative diseases, the biology of different SG subtypes may be directly implicated in neurodegeneration. Here, we will discuss mechanisms of SG formation, their subtypes, and potential contribution to health and disease.

Keywords: ALS; C9orf72; FTD; Neurodegeneration; RBPs; Stress granules; TDP-43; Tau.

Fig. 1

A Individual RNPs reversibly assemble into cytoplasmic foci triggered by physiological and environmental stimuli. The ‘liquid–liquid’ phase separations (LLPs) into phase-dense foci are driven by weak and transient intermolecular interactions that are enriched in RBPs containing LCDs and IDPRs. Persistent RNP-inducing stimuli promote interactions between assembled RNPs to form denser, less liquid–liquid, ‘gel-like’ phase. B Cellular stress induces cytoplasmic nanoscopic SG seeds, enriched in RBPs, via electrostatic interactions. The consequent inhibition of protein synthesis reversibly recruits non-translating mRNPs and additional RNA binding proteins to SG foci. The growth of phase separation results in the formation of mature and microscopic biphasic SGs consisting of more stable, less dynamic ‘core’ surrounded by less stable, more dynamic ‘shell’. The assembled SGs are in dynamic equilibrium with the surrounding polysomes. Removal of stress leads to resumption of protein synthesis and disassembly of SGs. The mRNPs are targeted for translation, thus causing the SGs to reduce in size and number to form nanoscopic SG seeds

Fig. 2

Stress-specific proteomic (A) and transcriptomic (B) heterogeneity defines SG sub-types and dynamics. Stress induced canonical stress granules can be either (a) p-eIF2α dependent triggered through stress-activated eIF2α kinases (GCN2, HRI, PERK or PKR) or (b) p-eIF2α independent (by mTOR activation or eIF4A inhibitors). Global translational repression prompts reversible recruitment of non-translating mRNPs and other proteins to SGs. Key SG components include poly(A) mRNAs, translation machinery components and RBPs (shown in red). The canonical stress granules are more dynamic and cytoprotective in nature. p-eIF2α independent SGs induced by glucose starvation, chemotherapeutic drugs, UV and other xenobiotic agents usually lack one or more key components of the canonical SGs. A common feature of non-canonical p-eIF2α independent SGs, which are less dynamic and cytotoxic, is the absence of translation initiation factor eIF3 (right panel, shadowed). B The stress-specific transcriptomic heterogeneity among SG is a function of differential association of mRNAs with RBPs. p-eIF2α dependent heat shock and oxidative stresses promote increased targeting of long poorly translated mRNAs (blue and green) to SGs, while ER stress causes preferential association of mRNAs with AU-rich elements (red and yellow) to SGs. At the same time, p-eIF2α independent non-canonical granules are depleted of mRNAs associated with eIF3 (purple)

Fig. 3

Maturation of physiological SGs into pathogenic aggregates is mainly driven by chronic stress and mutant RBPs and/or RNA repeats, with progressive impairment of their physiological clearance. Stress mediated assembly of untranslating mRNPs into microscopic canonical, dynamic and less stable SGs is assisted by RNA and RBPs. Specific stress conditions result in the formation of non-canonical cytotoxic SG subtypes. Genetic mutations in LCDs/IDPRs/ RNA-binding motifs of RBPs (TDP-43, FUS, EWS, Ataxins, hnRNPA1, hnRNPA2/B1TAF15 and TIA-1/R; see Table 1) and/or their post-translational modifications (PTMs) further shift maturation of SGs into non-canonical, less dynamic and cytotoxic SG subtypes. Further, clearance of these SGs is reduced by inhibition of autophagy and/or mutation in the autophagy associated factor VCP (valosin-containing protein). Chronic localization of disease-linked defective RBPs, ALS/FTD-associated dipeptide repeats (DPRs) and components of sequestosome (e.g. sequestosome protein 1 or p62/SQSTM1) promote transition to insoluble, more fibrillar and persistent pathological SGs. Points of therapeutic interventions (shown in red) target SG assembly, maturation and clearance. ASO anti-sense oligo(s), KD knock-down