Stress granules as a central hub linking organelle stress, aging, and neurodegeneration

Abstract

Stress granules (SGs) are dynamic cytoplasmic assemblies composed of RNAs and proteins that form in response to cellular stress, serving to halt translation and protect cellular integrity. In neurons, SGs mediate adaptive, pro-survival responses to acute stress; however, their dysregulation has been increasingly associated with both aging and neurodegenerative diseases. Aging neurons frequently exhibit changes in SG dynamics–with an increased propensity to form SGs while displaying reduced efficiency in their clearance–resulting in persistent granules that can facilitate the accumulation of pathological protein aggregates (e.g., TDP-43 or tau). Aberrant SG formation and defective clearance mechanisms are implicated in the pathogenesis of key neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer’s disease (AD), and Parkinson’s disease (PD). Recent findings have shown that SGs interface with organelles such as lysosomes, mitochondria, and the endoplasmic reticulum, utilizing autophagic and other protein quality-control mechanisms for clearance. As these clearance pathways progressively decline with age, SGs can transition from promoting cellular adaptation to contributing to cellular dysfunction. In this mini-review, we examine how aging influences SG biology, detail the role of SGs in neurodegenerative diseases, and discuss emerging mechanistic insights and therapeutic strategies aimed at modulating SG dynamics in the context of brain aging.

INTRODUCTION

SGs are transient cytoplasmic assemblies of mRNAs and proteins that are formed when translation is inhibited in response to stress. Composed of stalled 40S ribosomal subunits, translation factors, and multiple RNA-binding proteins (RBPs) such as G3BP1, TIA-1, and PABP1, SGs are generated via liquid–liquid phase separation involving the low-complexity domains of these RBPs (1). By sequestering both mRNAs and components of the translation apparatus, SGs function as a central node in stress-response: they suppress protein synthesis globally while determining mRNA destiny (storage, reinitiation, or degradation) until normally is restored (2). In neural tissue, tight regulation of SGs is particularly critical. Neurons, being highly specialized and long-lived, frequently encounter stressors (such as oxidative stress, metabolic challenges, and protein misfolding) throughout the organism’s lifespan. Proper SG dynamics are essential for neuronal adaptation to acute injury; for instance, the formation of SGs may protect neurons by compartmentalizing misfolded proteins or deleterious RNAs during episodes of temporary stress (3). Under physiological circumstances, SGs disassemble after stress subsides, allowing previously sequestered mRNAs to return to translation and enabling restoration of standard cellular processes (1). However, when SGs fail to disassemble or form aberrantly, they may contribute to pathogenesis (1). Importantly, several RBPs that initiate SGs (including TDP-43, FUS, and Tau) are also among the proteins that pathologically aggregate in neurodegenerative disorders (1, 4). This observation has led to growing focus on the involvement of SGs in age-associated neurodegenerative conditions (5).

Aging is the most significant risk factor for the majority of neurodegenerative diseases, as it is associated with persistent, low-grade cellular stress (6). Recent work suggests that brain aging fosters the emergence of persistent or repeatedly assembling stress granules, which may subsequently promote or exacerbate pathological protein aggregation (1, 7). Notably, ongoing cellular stresses characteristic of aging can cause normally transient stress granules to become stable structures, thereby promoting the accumulation of disease-associated proteins (1, 4). Evidence supporting this model includes findings that neurons and glia in aged brains frequently show SG markers or RBP aggregates even without acute stressors, suggesting a possible connection between normal aging and early neurodegenerative pathology (7-10).

In this mini-review, we summarize recent progress in elucidating how stress granule biology interfaces with brain aging and neurodegenerative disorders. We begin by analyzing the impact of aging on SG dynamics and proteostasis within the nervous system. Subsequently, we highlight advances regarding SG involvement in select neurodegenerative diseases–ALS and FTD, AD, PD, and related conditions–with emphasis on findings from the last ten years. We then expand upon mechanistic insights that challenge the traditional view of SGs: rather than isolated cytoplasmic compartments, SGs communicate with organelles (such as lysosomes, mitochondria, and endoplasmic reticulum) and undergo clearance through autophagy and other cellular quality control mechanisms (5). These interactions illustrate how age-related compromises in proteostasis (for example, decreased autophagic efficiency or mitochondrial defects) exacerbate SG dysregulation, perpetuating a detrimental cycle (11). Finally, we assess the therapeutic potential of stress granules and highlight future research directions. The context‑ and disease stage‑dependent dual roles of stress granules in neurodegeneration–acting as “friends” during early, adaptive stress responses but becoming “foes” when they persist chronically–have motivated strategies aimed at both suppressing SG assembly (to prevent pathological aggregation) and enhancing SG formation (to support cell viability). We present representative examples of each approach and contend that optimal interventions may vary depending on disease context and stage (5). We further discuss emerging methodologies and interventions (ranging from phase-separation modulators to cutting-edge imaging and genetic platforms) designed to address current gaps in the field. Collectively, these findings reinforce an evolving model: stress granules represent a critical intersection of RNA regulation, proteostasis, and organellar stress responses in aging neurons, and targeting this intersection could unlock novel avenues for understanding and ultimately alleviating neurodegenerative pathologies. Essentially, SGs function as a double-edged sword in the aging brain: providing cytoprotective effects during acute stress, yet potentially serving as drivers of neurodegeneration when chronically unresolved. Aging shifts this equilibrium by fostering resilient SGs and hindering their removal, thus transforming SGs from protective factors to pathogenic drivers and creating conditions conducive to neurodegenerative disease. 

MAIN TEXT

Stress granules in the aging brain

Aging exerts a significant influence on cellular stress responses, and neurons are similarly affected. As organisms age, cells demonstrate modified dynamics of stress granules at both their assembly and disassembly phases (12). Evidence from cultures and model systems suggests that older cells assemble stress granules more quickly upon mild stress but remove them less efficiently once stress is alleviated (13, 14). For example, fully senescent human fibroblasts generated a substantially higher number of SGs under acute oxidative stress, and the clearance of SGs was markedly delayed in these cells compared with their younger counterparts (13). These findings imply that the proteostatic and signaling machinery essential for SG dissolution (such as chaperones, ATP maintenance, autophagy, and VCP/p97-mediated processes) decline in efficiency as cells undergo senescence. Supporting this concept, a review on stress granules and aging observed that older cells frequently contain “aberrant” SGs with extended persistence, which may disturb mRNA equilibrium and protein homeostasis (13). Consistent with these observations, aged C. elegans demonstrate altered localization of SG-associated proteins and formation of RNP granules even in unstressed conditions. Notably, the RNA-binding protein TIAR-2 (the C. elegans homolog of mammalian TIAR/TIA-1) redistributes from the nucleus to cytoplasmic, granule-like structures in older worms, a response not observed in young worms exposed to the same mild stress (15). This age-related shift of RBPs into granules points to a decreased threshold for SG formation in aged neurons, likely resulting from cumulative molecular damage or continually activated integrated stress response. In Drosophila, natural aging also leads to the gradual aggregation of cytoplasmic RNP factors into large but still dynamic granules, a process dependent on increased amounts of the conserved DEAD-box helicase Me31B/DDX6 and PKA signaling (7). These age-related assemblies sequester selective mRNAs and translational regulators, indicating that normal aging reconfigures neuronal RNP condensates toward more persistent, stress-granule-like states.

Aging is also associated with a reduction in the removal of SGs and their components. The activities of autophagy and the ubiquitin–proteasome system, which are responsible for degrading long-lived proteins and even entire SGs (referred to in some cases as “granulophagy”), decline as organisms age. As a result, proteins that are typically present only transiently in SGs may persist, leading to aggregation. For instance, neurons from aged mice and humans exhibit accumulation of insoluble cytoplasmic forms of the SG-nucleating RBPs TDP-43 and FUS, both of which normally shuttle between the nucleus and SGs during stress (16, 17). Chronic mislocalization of these proteins increases their tendency to form pathological aggregates, and aging appears to promote such mislocalization through both enhanced cellular stress (including oxidative DNA damage and metabolic stress) and diminished efficiency of mechanisms tasked with restoring RBP homeostasis. Supporting this, a recent investigation highlighted the lysosome-interacting protein NCOA7 as an important regulator of SG clearance whose expression decreases with age–aged cells with lower NCOA7 exhibited defective autophagic degradation of SGs and buildup of SG markers, whereas elevating NCOA7 (or enhancing autophagy) improved SG clearance and mitigated cellular senescence (14). Collectively, these observations indicate that aging cells not only generate SGs more readily but also exhibit impaired resolution, leading to more frequent and long-lasting SGs as time progresses (Fig. 1).

Fig. 1.

Aging: stress granules—from shields to seeds. The characteristics of stress granules (SGs) change across the lifespan: Left (Aging brain)—SGs form more frequently and tend to increase in size even under mild stress conditions, while their clearance by autophagy (p62/NCOA7-dependent) and chaperone systems (VCP/p97) is compromised, resulting in persistent SGs that promote the accumulation of pathological aggregates such as TDP-43, FUS, and tau. Right (Young brain)—SGs are typically transient and cytoprotective: they rapidly assemble during acute stress episodes and are effectively disassembled during recovery through robust autophagy–chaperone networks, limiting sustained sequestration of RNAs and proteins.

Recent research also indicates that chronic low-level stress signaling in aging neurons persistently activates the eIF2α kinase pathway (such as through PKR), which results in sustained translation repression and SG formation, even in the absence of acute insults (18). Increased cytosolic double-stranded RNA in aged neurons (which may arise from retrotransposon activation or aberrant mitochondrial transcripts) can stimulate PKR and promote continuous SG assembly, effectively placing the aged neuron in a constant state of “standby stress response” (19). Although this persistent SG presence is initially adaptive, it can become detrimental by sequestering mRNAs and RBPs for prolonged periods. Notably, aged neurons frequently display characteristics of “pre-stressed” cells: they contain SG-like RNP inclusions under basal conditions and are unable to elicit appropriate SG responses to additional acute stressors (19). Studies have shown that aged neurons commonly exhibit a significant reduction of particular RNA-binding proteins, especially spliceosomal factors, and that TDP-43 and other splicing proteins are abnormally mislocalized to the cytoplasm. In normal circumstances, these cytoplasmic splicing factors would be transiently sequestered into SGs during stress; by contrast, chronic stress in aged neurons disrupts this protective sequestration, likely due to compromised ubiquitination machinery and decreased HSP90 chaperone activity (20). This prolonged hypotranslational state decreases the capacity of aged neurons to withstand further insults, as shown by their failure to manage subsequent stress without sustaining cellular damage.

In vivo studies utilizing animal models further substantiate the association between normal brain aging and SG dysregulation. Transcriptomic and proteomic analyses indicate that aging brains upregulate stress-response pathways and acute-phase proteins known to facilitate SG formation (for example, elevated G3BP1), while simultaneously downregulating select SG-clearance components (such as specific autophagy receptors and VCP cofactors) (20-23). For instance, a comprehensive single-cell transcriptomic analysis of mouse brain aging demonstrated increased expression of numerous stress response genes within aged neurons and glia (21). Consistently, proteomic co-expression network analyses of aging mouse brains have identified protein modules characterized by upregulation of stress-associated and immune-related functions (22). In Drosophila, the aging process induces progressive condensation of neuronal RNP granules (as previously described), highlighting an evolutionarily conserved tendency towards SG-like structures in aged neurons (7). In murine models, by 18–24 months of age (corresponding to late middle to old age), neurons display persistently elevated basal levels of phosphorylated eIF2α and pre-assembled SG proteins (including G3BP1 and Caprin1), even in the absence of extrinsic stressors, consistent with a constitutively activated integrated stress response observed in the aged brain (20). These collective data support the hypothesis that the aged brain predominantly exists in a pro-SG, hypotranslational state. At the same time, SG behavior in the aged brain is likely to differ between neurons and glial cells (24). In neurons, age‑related SG dysregulation primarily disrupts synaptic and axonal proteostasis: persistent, poorly cleared granules sequester mRNAs and RNA‑binding proteins that are required for local translation at dendrites and axon terminals, impairing activity‑dependent protein synthesis, synaptic remodeling, and long‑range axonal maintenance (25, 26). In addition, chronic SG‑associated defects in nucleocytoplasmic transport and protein quality control can facilitate the misfolding and aggregation of neuron‑specific client proteins, further compromising neuronal resilience to additional insults (27, 28). By contrast, in astrocytes and microglia, stress granules in the aged brain are more tightly intertwined with metabolic and inflammatory signaling pathways (24, 29, 30). Their formation and persistence can alter how these glial cells sense and integrate cytokines and danger‑associated signals, reshaping the production of inflammatory mediators, reactive oxygen and nitrogen species, and trophic factors (31-33). As a result, glial SG dysregulation may skew neuroimmune responses toward a chronic, maladaptive state and impair key homeostatic functions such as metabolic support, glutamate clearance, phagocytosis of debris, and synapse pruning, thereby indirectly exacerbating neuronal vulnerability (24, 29, 34). Importantly, aging remains the greatest risk factor for AD, PD, ALS, and the majority of neurodegenerative disorders, which implicates SG dysregulation as a potential mechanistic link driving age-related neuropathology. The progressive accumulation of persistent SGs or SG-derived protein aggregates could serve as nucleation sites for pathological inclusions and impair RNA metabolism in neurons, thereby exacerbating neurodegenerative progression (35).

While aging generally promotes increased SG formation and persistence, notable exceptions have been observed. For example, some senescent cells demonstrate reduced SG formation owing to lower expression of essential SG nucleators (e.g., G3BP1, TIA-1), or exhibit sustained eIF2α phosphorylation without SG assembly, suggesting the engagement of alternative stress-adaptive pathways (36, 37). Furthermore, prolonged exposure to low-level stress may paradoxically condition cells such that subsequent acute stress induces little or no SG formation (38). These scenarios underscore the complex regulation of SG dynamics. However, the prevailing pattern is that aging cells undergo more frequent and persistent SG formation due to accumulated stress and compromised proteostasis, which can subsequently promote pathological aggregate formation and exacerbate neurodegenerative progression.

Stress granules in neurodegenerative diseases

ALS and FTD (TDP-43 proteinopathies): The association between SGs and neurodegenerative disease was initially discovered in ALS and FTD, both of which commonly display cytoplasmic aggregates of TDP-43–an RBP that routinely transits through stress granules. In ALS/FTD, mutated or mislocalized TDP-43 (as well as, in some cases, FUS or hnRNP A1) accumulate to form insoluble inclusions within neurons (39). For many years, it was proposed that persistent stress granules may act as direct precursors (“niduses”) for such inclusions, a concept strongly reinforced by recent experimental evidence. For instance, live-cell imaging conducted in neuron-like cells has revealed that, under persistent stress conditions, SGs harboring TDP-43 progressively transition into stable aggregates, especially when degradation mechanisms are compromised. Furthermore, a recent investigation showed that TDP-43 aggregation in cells only occurs following a “double hit”: a markedly increased local concentration of TDP-43 within SGs, together with oxidative stress, both of which induce an “intra-condensate demixing” phase transition– leading to a TDP-43–enriched sub-compartment of the SG that ultimately solidifies into a pathogenic aggregate (40). Intriguingly, preventing SG assembly can paradoxically worsen neurodegeneration: another study employed a viral protein (alphavirus nsP3) to selectively block SG assembly by trapping G3BP, while leaving the upstream stress response intact (27). In both cellular and Drosophila models of ALS/FTD, suppression of SG formation promptly intensified neurodegenerative phenotypes (27), implying that SG formation has a protective role in regulating proteotoxic stress in these disease contexts. Collectively, these observations lend support to the hypothesis that transient SGs initially safeguard neurons by sequestering harmful RBPs, whereas either the inability to form SGs or their chronic persistence can promote pathology, especially in ALS/FTD cases involving TDP-43 mutations or C9orf72 repeat RNA stress.

On the other hand, excessive or persistent SGs evidently contribute to pathological processes in ALS/FTD. Mutations in several SG-nucleating RBPs (TDP-43, FUS, TIA-1) are associated with familial ALS/FTD, frequently resulting in enhanced aggregation propensity of these proteins. Furthermore, intermediate-length polyglutamine expansions in the SG protein ataxin-2 (ATXN2)–a recognized genetic risk factor for ALS– abnormally sequester TDP-43 in immobile RNP condensates, consequently impairing TDP-43’s axonal transport and facilitating its mislocalization (41). One prominent example is TIA-1, an RBP critical for SG assembly: in a mouse tauopathy model, genetic reduction of TIA-1 (and the resulting impairment in SG formation) ameliorated tau pathology and neuronal death (42). TIA-1 seems to directly bind tau and promote its incorporation into stress granule-like structures; in the absence of TIA-1, tau showed reduced propensity for toxic oligomerization. This supports the concept that persistent SGs (or SG components such as TIA-1) can drive pathological aggregation of disease-associated proteins, representing a “foe” function. In ALS models, ongoing cellular stress results in SGs that persist and act as nucleation sites for irreversible TDP-43/FUS aggregation (43). For instance, in C9orf72-linked ALS/FTD, arginine-rich dipeptide repeat proteins arising from repeat expansions interact with the SG scaffold protein G3BP1 with approximately 1,000× greater affinity than RNA, promoting excessive phase separation and enabling a gradual transition of SGs into Thioflavin-positive solid aggregates that recruit TDP-43 and other RBPs (44). Post-mortem studies of ALS patient brains reveal that SG-associated proteins (e.g., HuR) co-localize with early TDP-43 aggregates, while the autophagy receptor p62 is found with mature TDP-43 inclusions (45, 46). Thus, these findings support the hypothesis that pathological inclusions in ALS/FTD may arise from unresolved stress granules that fail to be efficiently degraded.

Emerging evidence underscores the importance of timing: acutely, SG formation in ALS models affords a protective effect by buffering cells from immediate proteotoxic stress, whereas chronically, the inability to efficiently clear SGs renders them harmful. Consistent with this view, recent studies in ALS/FTD and related neurodegenerative models have shown that experimental suppression of SG assembly can paradoxically exacerbate neurodegenerative phenotypes, whereas modulating SG dynamics and their resolution mitigates neuronal loss, underscoring the disease‑stage dependence of SG function (30). This therapeutic perspective highlights the importance of facilitating SG resolution instead of merely suppressing SG formation. For example, enhancing VCP/p97 activity, which is involved in the disassembly of RNP granules, or promoting autophagy in ALS models, leads to decreased TDP-43 aggregate burden and increased neuron viability (47-49). Likewise, stimulation of the heat shock response—such as with arimoclomol to induce chaperone expression—facilitates the clearance of TDP-43 and ubiquitin aggregates in ALS models, thereby reducing neuropathological changes (49).

In summary, ALS and FTD illustrate both the protective and pathological roles of SGs in disease: SGs act as transient buffers against acute cellular insults, but persistent SGs resulting from mutant RBPs or other stressors can become pathogenic factors in neurodegeneration. Achieving a balance between these contrasting effects remains central to ALS/FTD research, emphasizing the need to precisely regulate SG dynamics for effective therapeutic intervention.

AD (tau proteinopathy): AD is characterized by the presence of extracellular amyloid-β plaques and intracellular tau neurofibrillary tangles. While AD has not traditionally been classified as an RBP proteinopathy, accumulating evidence suggests that dysregulation of SGs also contributes to AD pathogenesis. Tau, the microtubule-binding protein that aggregates in AD, has demonstrated interactions with SG proteins. Importantly, TIA-1, a major SG constituent, directly binds tau and is co-localized with hyperphosphorylated tau within neurofibrillary tangles in AD brain tissue, where it facilitates tau aggregation and fibril formation (42, 50). In a pivotal 2018 study, genetic reduction of TIA-1 in P301S tau-transgenic mice disrupted the assembly of SGs, decreased the accumulation of soluble toxic tau oligomers (while encouraging the formation of less toxic fibrillary tangles), and resulted in marked neuroprotection along with extended survival and enhanced behavior (42). These findings indicate that TIA-1–dependent SGs facilitate tau misfolding by concentrating tau and RNA-binding proteins within a specialized microenvironment that promotes the formation of toxic oligomers, elucidating a mechanism by which SGs serve as “foes” in tauopathy (42, 51).

Conversely, other SG components can exert protective effects. For instance, G3BP1 and G3BP2, the primary nucleators of SGs, interact with a wide array of neuronal mRNAs including those implicated in AD that are associated with proteostasis (52, 53). Experimental studies have demonstrated that G3BP1 reduces protein aggregation in Huntington’s disease models, and that inhibition of SG formation through G3BP sequestration intensifies neurodegenerative manifestations in several disease models (54, 55). Supporting this, a more recent study reported that disruption of SG assembly (by viral sequestration of G3BP) led to aggravated neurodegenerative symptoms in ALS, FTD, and ataxia models (27). Additional evidence from transcriptomic analyses in neurons shows that SGs preferentially capture mRNAs encoding proteins responsible for molecular folding, protein quality control, and cellular proteostasis—including many factors associated with AD (52). Gene network analysis of mRNAs enriched in SGs indicates an overrepresentation of pathways involved in protein homeostasis, molecular chaperones, and the ubiquitin-proteasome system, suggesting that SGs regulate the bioavailability of crucial proteostasis factors during cellular stress (52, 55).

A recent and important discovery is that chronic stress and disrupted SG dynamics can promote the acceleration of tau pathology in vivo. In wild-type tau mice, extended periods of stress resulted in sustained SG formation, which was associated with elevated tau hyperphosphorylation and aggregation (56). Moreover, genetic disruptions that impede SG disassembly, such as mutations in SG-associated RBPs, intensify tau pathology, indicating that impaired SG clearance may facilitate the misfolding and aggregation of even wild-type tau (56). Importantly, the amyloid-β₄₂ peptide linked to AD was recently demonstrated to induce SG formation through the PKR-eIF2α stress kinase pathway, thereby providing a direct mechanistic connection between amyloid pathology and SG dynamics (57).

Taken together, these observations underscore the complex, dual role of SGs in AD and related tauopathies. In AD, transient SGs in early stages likely act as cytoprotective buffers, whereas chronically persistent ‘pathological’ SGs in later stages disrupt nucleocytoplasmic transport and promote proteotoxic aggregation (24, 58). Whether SGs have detrimental or protective effects likely depends on their specific protein composition and dynamic properties, especially the interplay between neurotoxic elements such as TIA-1 and neuroprotective components like G3BP1/G3BP2. Additionally, SGs have been identified in glial cells, including microglia and astrocytes, during AD-related inflammatory responses, where they may disrupt normal glial function (59-61). Overall, while SGs do not constitute a primary hallmark of AD, they are a significant secondary pathology capable of modulating disease progression via interactions with tau and other aggregating proteins and by affecting neuroinflammatory processes.

PD and related disorders: In contrast to ALS and AD, the involvement of stress granules in PD is less thoroughly understood; however, there has been increasing attention in this area recently. PD is characterized by aggregates of α-synuclein (Lewy bodies) and degeneration of dopaminergic neurons, commonly accompanied by oxidative stress and mitochondrial dysfunction—both of which are established inducers of SG formation. Among the PD-associated proteins, DJ-1 (PARK7) serves as a key mediator linking PD pathology to SG biology. DJ-1 functions as an antioxidant chaperone, and mutations in this protein are implicated in certain familial forms of PD. Experimental evidence demonstrates that wild-type DJ-1 localizes to SGs and processing bodies during cellular stress, where it binds mRNAs and components of SGs (62). In neuronal model systems, DJ-1 showed rapid translocation to SGs in response to oxidative or excitotoxic challenges (62). Importantly, disease-associated DJ-1 mutations that impair its function also disrupted this translocation process, resulting in greater susceptibility of cells to stress-induced death (62). These findings indicate that DJ-1 mediates neuroprotection, at least in part, by regulating RNA granule dynamics, and that dysfunction in DJ-1 compromises SG homeostasis, thereby contributing to PD pathogenesis.

One of the most notable recent advances is the emergence of evidence indicating that modulation of SG pathways can ameliorate Parkinsonian phenotypes in vivo. In 2025, Fang et al. demonstrated that perillaldehyde (PAE)–a natural compound derived from herbal extracts–provides neuroprotection in PD models through enhancement of SG formation (63). PAE interacts with G3BP1/2 to facilitate SG assembly, thereby improving the cell’s ability to respond to stress. In both C. elegans and mouse PD models, administration of PAE led to substantial SG induction, elevated eIF2α phosphorylation, and, importantly, provided significant protection for dopaminergic neurons against neurotoxic challenges (63, 64). Animals receiving PAE exhibited lower levels of α-synuclein aggregation and demonstrated improved motor performance compared to untreated counterparts (64, 65). Notably, the neuroprotective capacity of PAE was abolished when SG formation was genetically inhibited (through G3BP or TIAR-1 knockdown in worms) (27, 63), demonstrating that SG assembly is essential for its protective effects. Therefore, enhancing the SG response may have therapeutic potential in PD, possibly by sequestering aggregation-prone α-synuclein or by controlled activation of the integrated stress response. This is in contrast to ALS/FTD, where approaches to dissolve SGs are being investigated, underscoring the disorder-specific functions of SGs.

Other research using PD models has established connections between SGs and established pathogenic mechanisms. For instance, mislocalized α-synuclein is capable of binding RNA and may disrupt normal SG assembly (66, 67). Furthermore, some investigations report that α-synuclein aggregates can sequester crucial SG proteins, thereby hindering typical SG biogenesis. LRRK2, a kinase mutated in PD, has been shown to phosphorylate various translation factors and RBPs, which may influence the dynamics of SG assembly (68, 69). In addition, prolonged mitochondrial stress within dopaminergic neurons is likely to promote sustained SG assembly; impaired mitochondria have the potential to release abnormal RNA species that activate PKR and initiate the SG/ISR pathway (19, 70).

Chronic neuroinflammation is also integral to PD pathogenesis. Pro-inflammatory cytokines, including TNF-α and IFN-γ, are capable of driving SG formation in neurons and astrocytes, whereas oligodendrocytes develop persistent SGs only when exposed to both inflammatory cues and metabolic stress (29, 71, 72).These observations are consistent with the pro-inflammatory environment documented in PD brains, which is characterized by activated microglia and increased cytokine levels (73).

In summary, while SGs have not been as comprehensively investigated in PD as in ALS or AD, available evidence indicates that SGs arise at the convergence of oxidative stress, mitochondrial impairment, and protein misfolding—all of which are pivotal to PD pathogenesis. Interventions that enhance SG-mediated stress adaptations (such as PAE administration) or facilitate proper SG turnover could confer neuroprotection in PD. However, the persistence of SGs (notably in aged dopaminergic neurons with cumulative injury) may facilitate α-synuclein aggregation. This dualistic behavior deserves further study, but accumulating data show that impaired regulation of SGs constitutes a significant factor relating cellular stress to neurodegeneration in PD. (Although not thoroughly addressed in this discussion, emerging evidence points to SG dysfunction as a frequent hallmark of numerous protein-misfolding neurodegenerative diseases, including Huntington’s disease and prion disorders.)

Integrative mechanisms: organelle interactions and sg clearance

A significant advance in the past decade is the recognition that stress granules do not act independently. Rather, they continuously interact with multiple organelles and stress-response pathways, establishing a coordinated cellular network. In this section, we explore mechanisms by which SGs associate with organelles—especially lysosomes, mitochondria, and the endoplasmic reticulum (ER)—and examine how aging alters these processes. We further review how SGs are eliminated by cellular quality control systems and assess the impact of age-related decline in these systems on the persistence of SGs.

Crosstalk with lysosomes and autophagy: Lysosomes, which function as the cell’s major degradative organelles, maintain a reciprocal association with SGs. Autophagy, on one hand, is essential for the removal of aberrant or long-lived SGs. These SGs are recognized by autophagy receptors (e.g., p62/SQSTM1) and subsequently transported to lysosomes for degradation—a process known as granulophagy (74, 75). This pathway is vital in neurons, where ongoing autophagy is required for maintaining proteostasis and cell viability (76, 77). During aging, the efficiency of neuronal autophagy diminishes, which probably leads to increased accumulation of SG “debris” (1, 78). Notably, stimulation of autophagy enhances the clearance of SG markers in both cellular and neuronal systems (74, 79). In alignment with these findings, Wolozin and Ivanov (2019) propose that impairments in autophagy during aging permit SGs to persist and potentially promote pathogenic processes (1).

On the other hand, emerging research has demonstrated that lysosomal damage can directly initiate SG assembly as a cellular defense mechanism. Recent investigations indicate that lysosomal injury promotes SG formation through several coordinated mechanisms. When the lysosomal membrane is compromised, autophagy-related proteins such as LC3 and GABARAP rapidly bind to the damaged membrane (a process termed Atg8ylation), recruiting key SG nucleators including G3BP1 and NUFIP2 to the lysosome surface. This recruitment suppresses local protein synthesis and inhibits mTORC1 signaling (80). Concurrently, SG condensates can physically form a “plug” at the site of membrane disruption, thereby preventing the escape of lysosomal contents until membrane repair proteins, such as the ESCRT machinery, restore membrane integrity (81). Furthermore, lysosomal rupture induces a localized Ca^2＋-increase, which activates PKR kinase via the Ca^2＋-sensor ALIX, resulting in spatially restricted eIF2α phosphorylation and SG assembly on damaged lysosomes (82) (Fig. 2). By promptly halting local protein translation and sealing membrane breaches, these lysosome-induced SGs enable cells to withstand acute lysosomal injury.

Fig. 2.

Stress granule hub: crosstalk with lysosomes, ER, and mitochondria. Stress granules (SGs) act as organelle-stress hubs, coordinating interactions among lysosomes/autophagy, the endoplasmic reticulum (ER), and mitochondria. Top (grey): lysosomal damage initiates localized SG assembly through Ca^2＋‑PKR signaling; SG condensates contribute to membrane stabilization at rupture sites and temporarily inhibit protein translation, whereas granulophagy typically clears SGs following repair—a process often impaired in ALS and aging, resulting in sustained SG presence. Left (beige): at the ER, PERK–eIF2α signaling promotes SG formation, and Annexin A11–mediated coupling positions SGs at specific ER subdomains, thereby attenuating secretion and supporting ER proteostasis. Right (green): mitochondrial oxidative stress (ROS) and integrated stress response activation (eIF2α phosphorylation) stimulate SG assembly; SGs, in turn, regulate metabolism by limiting fatty-acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) to promote cell survival and direct the mitophagy of compromised mitochondria. Overall, this schematic emphasizes the reciprocal communication between SGs and these organelles, and demonstrates how disruptions in SG clearance or signaling channels can transform this adaptive network into a pathological driver in the aging or diseased brain.

In summary, SG interactions with lysosomes reveal an intricate synergy: SG assembly can be directly elicited by lysosomal stress, and, in turn, SGs contribute to lysosomal repair by both sealing membrane defects and suppressing mTORC1 activity to facilitate restoration. These insights broaden our understanding of SGs from passive cytoplasmic granules to active mediators of organellar stress adaptation. As lysosomal dysfunction becomes increasingly prevalent with aging and in neurodegenerative diseases (for instance, due to the buildup of undigested substrates or lipofuscin in neurons), the recently identified SG–lysosome interplay suggests that enhancing SG-mediated responses to lysosomal insults—or preventing their impairment—may offer therapeutic benefit in the aging brain.

Mitochondrial metabolism and mitophagy: Mitochondria are another organelle that closely interacts with SG biology. Cellular energy status and translational control are tightly connected, and both SG assembly and disassembly require ATP; in addition, SGs can exert reciprocal effects on cellular metabolism. Amen and Kaganovich (2021) demonstrated direct physical and functional interactions between SGs and mitochondria during nutrient stress (83). Under glucose starvation, SGs were found to dock on the outer mitochondrial membrane. These SGs interact with mitochondrial voltage-dependent anion channel (VDAC) pores and suppress their function. Because VDAC channels normally facilitate the entry of metabolites, such as fatty acids, into mitochondria for oxidative metabolism, SG-mediated VDAC inhibition reduces fatty acid β-oxidation (FAO) under nutrient deprivation. This adjustment provided a physiological advantage by conserving fatty acids for extended energy demands and lowering mitochondrial Reactive oxygen species (ROS) generation. When cells were unable to form SGs, either due to knockout of SG proteins or ALS-associated RBP mutations, they failed to inhibit FAO during starvation, resulting in increased ROS levels and cellular injury. Collectively, these findings indicate that SGs serve as metabolic regulators that preserve energy stores and mitigate oxidative stress by influencing mitochondrial substrate import. In neurodegenerative conditions, which are characterized by metabolic disturbances and heightened oxidative injury, this SG-mediated function may be neuroprotective. For instance, in ALS patient-derived cells harboring SG-protein mutations (such as in TIA1 or FUS), disrupted SG dynamics may impair this metabolic adjustment and increase neuronal susceptibility to energy deficits and ROS-mediated injury (83-87). During aging, neuronal mitochondria exhibit diminished bioenergetic function and increased ROS production (88, 89). While SGs may help maintain metabolic stability in early life, impaired SG function during aging could worsen metabolic challenges.

Beyond its role in metabolism, recent studies have implicated SGs in mitophagy – the selective autophagic removal of damaged mitochondria. Huang et al. (2025) uncovered an unexpected association involving the SG protein PABPC1 (90). Under stress conditions, cytosolic PABP undergoes SUMOylation, which facilitates SG assembly. SUMOylated PABPC1 within SGs specifically isolates and stabilizes mRNAs encoding principal mitophagy receptors (such as FUNDC1 and BNIP3L/NIX). This mechanism protects these mRNAs from degradation, allowing for their translation after stress resolution, which enables synthesis of mitophagy proteins. In cancer cell models, this regulatory axis supported mitochondrial quality control during hypoxia or chemotoxic stress, thereby linking SG assembly to enhanced mitophagy. While this investigation was conducted outside the nervous system, it is probable that the pathway operates similarly in neurons: by regulating mRNA stability, SGs may promote the expression of mitophagy-related genes and facilitate the clearance of dysfunctional mitochondria. This function is particularly relevant in disorders such as PD, where defects in PINK1/Parkin-driven mitophagy result in accumulation of damaged mitochondria and increased oxidative stress (91-94). Should SG formation and the associated mRNA sequestration be compromised in aged neurons, insufficient expression of mitophagy receptors could contribute to the accumulation of dysfunctional mitochondria and subsequent cell loss. On the other hand, agents that promote SG formation (such as PAE, as described above) have also been shown to increase eIF2α phosphorylation and induce ATF4 target gene expression (63), which may further enhance adaptive stress responses including mitophagy.

Mitochondria can also trigger SG formation through mechanisms unrelated to metabolism. For example, when mitochondria are under stress, they may release double-stranded RNA (mt-dsRNA) into the cytosol, which activates PKR and initiates the integrated stress response, consequently promoting SG assembly (19, 70) This phenomenon is observed during aging: senescent cells exhibit persistent leakage of mt-dsRNA that continuously primes SG formation (19, 95). In Huntington’s disease models, mutant huntingtin interacts with mitochondria and promotes mitochondrial RNA leakage, which aligns with the presence of SG-like structures in affected neurons (96-98). Therefore, mitochondrial dysfunction can drive SG formation, while SGs simultaneously adapt to and alleviate mitochondrial stress, establishing a feedback loop that is likely crucial in diseases marked by energy failure and oxidative injury (Fig. 2)

In conclusion, SGs and mitochondria participate in a bidirectional interaction. SGs regulate metabolism during stress—by modulating fuel oxidation and reducing ROS—and facilitate mitochondrial quality control through stabilization of mitophagy-related mRNA, whereas mitochondrial dysfunction signals (including metabolic changes, Ca^2＋, and dsRNA) promote SG formation. Disruption of this dynamic in aging and neurodegenerative conditions—either by excessive activation of SGs by dysfunctional mitochondria or by impaired SG formation—may compromise mitochondrial protection. Elucidating these interactions offers new therapeutic opportunities, such as integrating metabolic interventions with SG modulators to enhance neuronal resilience.

Endoplasmic reticulum and secretory pathway: The endoplasmic reticulum (ER) serves as a primary site for the synthesis of secreted and membrane proteins and operates in close coordination with the cytosolic translation machinery (99, 100). In Drosophila, stress granules have been observed to nucleate at discrete ER subdomains. For instance, the ER exit site scaffold Sec16 interacts with and stabilizes a phosphorylated form of the G3BP homolog Rasputin, thereby promoting SG assembly under amino-acid starvation conditions (101, 102). Conversely, SGs induced by arsenite or heat stress are assembled via pathways that do not involve Sec16, underscoring that SG assembly processes differ based on the nature of the stress. These observations indicate that SG formation may be intricately regulated by ER–Golgi machinery in a stress-dependent manner.

Chronic ER stress, mediated through the unfolded protein response (UPR), can itself trigger SG formation via PERK activation, which leads to eIF2α phosphorylation and subsequently inhibits translation (103, 104). During aging or disease, a sustained UPR may persistently maintain SGs at ER subdomains, such as ER exit sites. Moreover, in the context of acute cellular stress, SG formation can influence the function of the secretory pathway. For example, in mammalian cells exposed to arsenite, SGs recruit the multi-subunit TRAPP complex—an ER-to-Golgi tether—together with COPII coat proteins, which temporarily disrupts ER-to-Golgi trafficking and causes Golgi dispersal (105). Importantly, this process is observed exclusively in proliferating cells, where CDK1/2-dependent phosphorylation of the SG protein hnRNPK enables TRAPP to associate with SGs (105, 106). The involvement of TRAPP also alters SG structure: TRAPP-deficient cells generate smaller SGs lacking specific signaling proteins, such as RACK1 and mTORC1 components, rendering these cells more vulnerable to stress (Fig. 2) (105). Collectively, there is a reciprocal interaction between SGs and the secretory pathway: SGs have the ability to transiently pause protein secretion, while components of the secretory pathway modulate SG assembly and molecular composition. In neurons, which require extensive secretory capacity for the trafficking of neurotransmitters and membrane proteins, such crosstalk may be especially important. Acutely, inhibition of ER-to-Golgi transport during stress might protect neurons by preventing delivery of misfolded proteins to synaptic or extracellular compartments. Over extended periods, persistent SG–secretory pathway interactions could contribute to synaptic dysfunction, such as when sustained SG presence impedes the trafficking of receptors or growth factors. Furthermore, age-related alterations in ER or Golgi architecture—including Golgi fragmentation observed in neurodegenerative conditions—might, in part, result from chronic SG activity and its prolonged effects on the secretory system.

In summary, both the ER and the secretory network act as sources and targets in the regulation of SGs. SGs may originate at the ER, particularly under conditions of nutrient stress, and can in turn alter ER and Golgi function by sequestering essential trafficking components such as Sec16 or TRAPP. This evidence expands the traditional perspective on SGs, redefining them as integrative coordinators of complex cellular stress responses that encompass translational, metabolic, and secretory processes. Regarding aging and neurodegeneration, these insights suggest that persistent SGs may exacerbate ER stress and secretory dysfunction observed in pathological conditions, while ongoing ER disturbance could also promote maladaptive SG formation.

SG clearance mechanisms and aging

A crucial aspect yet to be fully elucidated is the mechanism by which cells clear SGs, and how this capacity deteriorates with age (1, 35). Under physiological conditions, when stress subsides, SGs disassemble and their constituent proteins redistribute into the cytoplasm or are transported back to the nucleus (107, 108). SG clearance is primarily mediated by two major pathways: the VCP/p97 AAA^＋ ATPase machinery and the autophagy–lysosome system (74, 109). The VCP/p97 complex functions as an ATP-dependent unfoldase, extracting proteins from assembled complexes to facilitate their disassembly (110, 111). VCP is directed to ubiquitinated SG components, such as ubiquitinated G3BP1 via the ER membrane adaptor FAF2, thereby promoting the dissolution of SGs (109, 112). In parallel, autophagy is capable of engulfing entire SGs or their fragmented components; cargo receptors like p62/SQSTM1 recognize ubiquitinated SG proteins and guide them for lysosomal degradation (a process referred to as “granulophagy”) (75, 113). Both the functional capacity of VCP and autophagic degradation efficacy diminish during aging, leading to compromised SG clearance (1, 35). As a result, senescent cells frequently retain persistent SG “cores” or RNP aggregates that remain long after stress resolution; these can be considered clearance-incompetent structures (107). Such stable condensates can promote subsequent protein aggregation (114). In primary neurons, the processes of aging or persistent stress result in reduced SG dynamics; for instance, aged mouse neurons or neurons previously subjected to mild stress exhibit impaired SG disassembly and delayed recovery (28, 115). At the mechanistic level, stimulating the VCP/p97 pathway (e.g., through ULK1/2-mediated VCP phosphorylation) enhances SG disassembly, while inhibition of VCP leads to its dysfunction (109, 112). In vivo, altering VCP cofactors influences proteostasis and can even modulate lifespan—upregulation of the VCP-interactor ubiquilin-1 in C. elegans (via HSF-1) is associated with increased lifespan and enhanced protein homeostasis (116). The capacity of chaperones also decreases with advancing age (e.g., reductions in HSF1/HSP networks), and chaperones such as HSP70 and HSPB8 (alongside the co-factor BAG3) play a direct role in SG disassembly and avert SG “hardening” (117, 118). Moreover, oxidative stress induces chemical modifications of low-complexity domains in SG proteins, thereby reducing their dynamics and increasing susceptibility to aggregation, which may account for the persistence of SG proteins under highly oxidative conditions such as PD (1, 119, 120).

SGs initially exist as dynamic liquid condensates, but under prolonged stress conditions or in the presence of disease-associated mutations, they can transition to gel- or solid-like states (120, 121). This phase conversion is regulated by post-translational modifications, whereby, for example, disease-associated TDP-43 hyperphosphorylation diminishes its liquid-like characteristics and favors the formation of fibrillar assemblies, while poly (ADP-ribose) binding (PARylation) enhances RBP coalescence, and a reduction in ATP levels with age (as ATP functions as a cellular hydrotrope) exacerbates SG hardening (122-126). Once these condensates become solidified, their clearance by chaperones, VCP, and autophagy is significantly impaired, resulting in the accumulation of persistent pathological aggregates (1, 118). For example, under stress, TDP-43 is recruited to SGs and can be cleaved by caspases into C-terminal fragments with a high propensity to aggregate, efficiently seeding amyloid assemblies (127-129). These defects in phase aging and clearance become more pronounced with advancing age, as SGs persist for longer durations and exhibit a loss of liquidity in aged cells and tissues (12, 35).

In the context of neurodegenerative diseases, multiple approaches have been developed to facilitate SG clearance, frequently by activating granulophagy through p62 and other relevant receptors (75). For instance, small-molecule autophagy inducers have shown to accelerate TDP-43 degradation and enhance neuronal viability, which leads to a reduction in SG/RNP pathology within ALS/FTD models (47, 130). In addition, compounds that augment VCP/p97 function are under investigation: a recently identified VCP activator has been reported to facilitate the removal of intranuclear TDP-43 aggregates in a multisystem proteinopathy model (131, 132). In contrast, broad-spectrum VCP inhibitors such as NMS-873 and CB-5083 disrupt p97 activity, and CB-5083 clinical trials in oncology were discontinued due to unexpected retinal toxicity resulting from PDE6 inhibition (133-135). Collectively, these data support the hypothesis that enhancing endogenous SG or aggregate-clearance mechanisms may mitigate disease by restricting aggregate initiation and propagation (136). Importantly, the timing of intervention appears to be critical: early or pre-symptomatic enhancement could potentially eliminate toxic seeds prior to their dissemination, while in advanced disease, a substantial aggregate load combined with age-associated autophagy decline may overwhelm even improved clearance mechanisms (47, 137).

In summary, efficient SG clearance is equally vital as precise assembly to maintain SG function in healthy cells. The clearance component of this regulatory balance diminishes with age, resulting in prolonged SG persistence and a heightened risk for pathological changes. Consequently, comprehensive interventions targeting SG-related neurodegeneration must address both the inhibition of detrimental SG formation and the restoration or emulation of efficient SG clearance observed in younger cells.

Therapeutic implications and future directions

The dual role of stress granules in neurodegeneration—providing both protection and contributing to harm—creates complexities as well as potential therapeutic targets. For instance, inhibiting or resolving persistent SGs could help to limit the formation of toxic aggregates, as evidenced by TIA-1 reduction mitigating tauopathy (42). Conversely, strategies that enhance the SG response may promote neuronal survival under severe stress conditions, as seen with perillaldehyde’s protective effects in PD models through SG induction (63). Reconciling these seemingly opposing strategies remains an open question. Current perspectives suggest that both the disease stage and cellular context are determinative. In the early or acute phases of disease, supporting SG assembly may allow neurons critical time to restore homeostasis, whereas during late or chronic phases, promoting SG clearance or inhibiting their pathological persistence may become paramount. This highlights the need for a therapeutic window or adaptive strategy—initially facilitating SG formation during brief stress episodes, but prioritizing SG disassembly and clearance as disease progresses.

The design of pharmacological agents that precisely modulate SG dynamics is promising yet presents significant challenges. Multiple early-stage candidate compounds have emerged. Lipoamide, a low-molecular-weight redox-active compound, was recently demonstrated to inhibit SG condensation by covalently modifying specific SG proteins (138). Mechanistically, it acts by stabilizing intrinsically disordered regions within RBPs, enhancing protein solubility. In ALS-related experimental models, lipoamide dissipated abnormal SGs and conferred neuroprotection, including the reversal of motor phenotypes in both fly and mouse TDP-43/FUS models. These findings suggest that targeting SG disassembly can be advantageous when SGs function as disease-promoting seeds. Notably, lipoamide showed preferential disruption of pathological SG condensation while preserving the physiological formation of stress granules during acute cellular stress, likely due to its specificity for redox-sensitive SG proteins—underscoring its potential as a selective therapeutic.

Conversely, perillaldehyde (PAE) represents an SG-enhancing therapeutic strategy. Through binding to G3BP1/2, PAE promotes the phase separation of SGs and facilitates SG assembly even in response to milder stress conditions (63). In PD models, this action intensified the integrated stress response (as indicated by eIF2α phosphorylation) and increased the expression of cytoprotective genes, resulting in neuronal protection and decreased α-synuclein accumulation. Importantly, although PAE demonstrated beneficial effects in models of synucleinopathy, it could conceivably have adverse effects in ALS models where SGs are already excessively persistent. This highlights the importance of patient stratification: SG-promoting therapies may be advantageous for conditions featuring an inadequate stress response or following acute insults (such as PD or some acute CNS injuries), whereas SG-dissolving therapies may be more appropriate for diseases associated with pathological SG accumulation (such as ALS, FTD, or certain tauopathies).

An alternative strategy involves targeting pathways that are either upstream or downstream of SGs, rather than directly targeting SGs themselves (1, 139). For example, interventions aimed at modulating the integrated stress response (ISR) have garnered increasing attention. Pharmacological agents such as ISRIB—which allosterically counteracts the effect of eIF2α phosphorylation on eIF2B—can alleviate persistent translational repression but still maintain the protective features of the cellular stress response (104, 140). In models of prion disease and tauopathy, adjustment of ISR signaling (with ISRIB in prion disease, and repurposing ISR inhibitors like trazodone or dibenzoyl methane in tauopathy) improved cognitive deficits and attenuated neurodegeneration, suggesting that chronic ISR/SG-mediated translational repression is pathogenic (141-144). Nevertheless, because ISRIB also inhibits eIF2a∼P-dependent SG assembly, its administration may disrupt the beneficial acute SG response, indicating that therapeutic timing (such as administration after the initial stress exposure) is essential (104, 139). In contrast, a strategy involving brief activation of the ISR—using compounds that transiently induce mild eIF2α phosphorylation or UPR signaling—can precondition neurons to improve resilience against subsequent insults, leveraging hormesis via SG/ISR pathways (144, 145). This form of preconditioning is reminiscent of the neuroprotective effects provided by exercise or caloric restriction, both of which promote adaptive stress responses (such as BDNF and Nrf2 induction, mitochondrial biogenesis, and autophagy activation (146).

Research on SG–organelle interactions suggests potential for combination therapy strategies, representing a shift in current paradigms. For instance, as SGs contribute to repairing lysosomal damage, therapies designed to enhance SG recruitment to compromised lysosomes or to stabilize SG “plugs” may help prevent cell death in disorders associated with lysosomal rupture (such as certain forms of stroke, traumatic brain injury, or Gaucher’s disease with parkinsonian manifestations). Additionally, the combined use of an SG modulator and an autophagy enhancer could yield synergistic effects: one agent promotes appropriate SG assembly while the other facilitates efficient SG clearance.

Technological advancements will play a critical role in implementing these concepts. Newly developed optogenetic tools enable accurate spatiotemporal manipulation of SG formation within model organisms. For example, prolonged optogenetic induction of SG-like condensates in mouse neurons ultimately resulted in neurodegeneration, strengthening the hypothesis that sustained SG stress is detrimental (147). In contrast, short-term optogenetic induction of SGs resulted in negligible cellular damage, illustrating the dual role of SGs as both protective and harmful agents. These advanced tools can be applied in vivo to assess how modulating SGs influences cognitive function in aging brains. Innovations in imaging technology (such as correlative light/electron microscopy and cryo-ET) now yield detailed visualizations of SG ultrastructure and their interactions with organelles, which may uncover “SG contact sites” that represent potential therapeutic targets (for instance, small molecules designed to modulate SG–mitochondria associations). Omics methodologies are also being optimized: proximity labeling techniques (APEX, BioID) facilitate comprehensive analysis of SG protein and RNA constituents, and adaptations for brain tissue are enabling confirmation of cellular findings in aged neural tissue (97, 148-151). A persistent challenge is the transient and variable nature of SGs in vivo (1). Enhanced intravital imaging strategies and improved inducible systems are helping to address this limitation: two-photon microscopy employing virally delivered TIA1-EGFP enables visualization of SG-like granules in mouse cortex, an optogenetic “opto-G3BP1” platform offers a reversible means to genetically induce SGs, and G3BP1-GFP transgenic mouse models permit ongoing assessment of SGs within tissues (147, 152, 153). With these advanced methodologies, investigators can track how SG characteristics are altered during aging and evaluate interventions aimed at reinstating a more youthful SG response (154).

From a clinical perspective, SG-associated biomarkers may serve as valuable tools to guide therapy. Concentrations of certain SG proteins in cerebrospinal fluid or blood have the potential to reflect chronic SG stress. Several SG proteins have been identified in patient biofluids and have demonstrated associations with disease: for example, TDP-43 in CSF or plasma (including exosomal TDP-43) has been found to possess diagnostic and prognostic relevance, FUS can be quantified in plasma exosomes, and additional SG-associated RBPs such as RBM45 are measurable in CSF (155-158). Upon proper validation, these biomarkers could facilitate patient stratification for SG-targeted therapies and the monitoring of therapeutic efficacy (159, 160).

Ultimately, advancing age shifts stress granules toward deleterious outcomes within this continuum, highlighting the necessity of reestablishing the equilibrium between SG assembly and clearance in the aging brain. Targeting this biological network—such as by sustaining translational homeostasis and organelle function through controlled SG regulation—may intercept early events that contribute to multiple downstream disease mechanisms. This comprehensive approach, grounded in current mechanistic understanding and empowered by emerging technologies, offers potential to catalyze novel therapeutic interventions for neurodegenerative diseases.

Conclusions and perspectives: In conclusion, SGs display both context- and time-dependency, serving an acutely protective function but contributing to chronic pathogenicity. Optimal therapeutic strategies focus on re-establishing dynamic homeostasis by facilitating rapid SG assembly during stress, preventing their persistence and aberrant protein aggregation, and strengthening endogenous clearance mechanisms (such as granulophagy and VCP/p97-mediated disassembly) (1, 74, 75). Accumulating evidence highlights the efficacy of phase- and context-specific combination therapies—such as the co-administration of SG-dissolvers and autophagy enhancers, or the sequential application of integrated stress response modulators —to alleviate maladaptive translational arrest while preserving acute protective responses (140, 161). Furthermore, conceptualizing neurodegeneration as a dysfunction of the RNA–protein stress-response network, with SGs centrally positioned, redirects focus upstream from isolated protein aggregation toward the maintenance of translational regulation and organelle health—an integrated approach that has the potential to yield novel therapeutic strategies (1).