Neuronal stress granules as dynamic microcompartments: current concepts and open questions

Abstract

Stress granules are cytosolic, membraneless RNA-protein complexes that form in the cytosol in response to various stressors. Stress granules form through a process termed liquid-liquid phase separation, which increases the local concentration of RNA and protein within the granules, creates dynamic sorting stations for mRNAs and associated proteins, and modulates the availability of mRNA for protein translation. We introduce the concept that neuronal stress granules act as dynamic cytosolic microcompartments in which their components differentially cycle in and out, monitoring the cellular environment. We discuss that neuronal stress granules have distinctive features and contain substructures in which individual components interact transiently. We describe that neuronal stress granules modulate protein expression at multiple levels and affect the proteoform profile of the cytoskeletal protein tau. We argue that a better knowledge of the regulation of stress granule dynamics in neurons and the modulation of their material state is necessary to understand their function during physiological and pathological stress responses. Finally, we delineate approaches to determine the behavior and regulation of critical stress granule organizers and the physical state of stress granules in living neurons.

Big tau: What, how, where and why

“…These data are consistent with a shift of expression from LMW tau during the growth phase to Big tau in adult and a possible enhancement of axonal transport by providing a higher degree of structural support with less resistance. There are other modes of controlling the shift from LMW tau to Big tau that include the binding of microRNAs to the 4a exon or other exon junctions that can affect the pattern of tau expression by stress granules that increase the ratio of Big tau (Moschner et al, 2014; Sohnel & Brandt, 2023). It is however difficult to make general conclusions because there are subtleties in the selective expression of Big tau even in the PNS.…”

Liquid–liquid phase separation in synaptopathies

“…141 SGs appear to be heterogeneous owing to different protein and RNA compositions depending on the particular organism, cell type, cell condition, and stressor. [142][143][144][145] SGs in neurons exhibit different characteristics to SGs in other cell types, contain substructures that can affect their function, and modulate protein expression in more complex ways. 142,146 4.1 | Maladaptive stress response is associated with neurological diseases Various studies have found that brief activation of the physiological stress system during learning promotes memory consolidation, 147,148 while chronic exposure to stress can damage the structure and function of the brain.…”

“…SGs appear to be heterogeneous owing to different protein and RNA compositions depending on the particular organism, cell type, cell condition, and stressor 142–145 . SGs in neurons exhibit different characteristics to SGs in other cell types, contain substructures that can affect their function, and modulate protein expression in more complex ways 142,146 …”

“…[142][143][144][145] SGs in neurons exhibit different characteristics to SGs in other cell types, contain substructures that can affect their function, and modulate protein expression in more complex ways. 142,146 4.1 | Maladaptive stress response is associated with neurological diseases Various studies have found that brief activation of the physiological stress system during learning promotes memory consolidation, 147,148 while chronic exposure to stress can damage the structure and function of the brain. 149 Chronic stress exposure can induce a series of changes at different levels, including molecular pathways at the synapse, activation of select neuronal projections within and among different areas of the brain, neuroarchitecture such as dendrite length and branching, and large-scale brain networks.…”

Stress Granule-Related Genes during Embryogenesis of an Invertebrate Chordate

“…The dynamic assembly of this membraneless foci in the cytoplasm, mediated by the overexpression of mRNA binding proteins, allows the temporary stop of translation initiation of selected mRNAs confined inside SGs, in order to prepare the cell for a future acute stress condition when mRNAs are rapidly released from SGs to codify the required proteins (Arribere et al 2011; Liu and Qian, 2014; Protter and Parker, 2016; Somasekharan et al, 2020). SGs consist in a core structure of key mRNA binding proteins and mRNAs, connected each other by strong interactions, surrounded by a less concentrated and more dynamic shell, in which proteins and mRNAs can be easily exchanged with other type of cytoplasmic foci, such as processing bodies (p-bodies) (García-Mauriño et al, 2017), where mRNAs undergo degradation, germ cell granules (Mukherjee and Mukherjee, 2021), for maternal mRNA storage during early development, and neuronal granules (Söhnel and Brandt, 2023), important for synaptic remodeling. The regulation of mRNA stability, therefore, plays a key role not only in stress responses but also in cell proliferation, differentiation, and development.…”