Synaptic Chaperone Dysfunction as a Convergent Mechanism in Neurodegenerative and Psychiatric Disorders

Abstract

The heat shock protein (HSP) family comprises six sub-families whose members participate in a wide array of cellular processes. This minireview focuses on three specific heat shock proteins: Hsp90aa and Hsp90ab from the Hsp90 sub-family, Hsc70 (Hspa8) from the Hsp70 sub-family, and the Hsp40 co-chaperone sub-family. In neuronal cells, these HSPs play critical roles in maintaining proper synaptic proteostasis. We have summarized current evidence for how these HSPs act independently and collaboratively to maintain synaptic proteostasis. Importantly, emerging data suggests that synaptic disruptions of Hsp90, Hsc70, or their Hsp40 partners not only contribute to hallmarks of neurodegenerative pathology but also contribute to psychiatric conditions such as depression and post-traumatic stress disorder (PTSD). By integrating findings across these two disease categories, we propose that dysfunctional chaperones at the synapse represent a molecular link between neurodegenerative and neuropsychiatric disorders.

Introduction

Maintaining protein homeostasis at synapses is essential for neural function.^1-3 Among the molecular systems that maintain proteostasis in the synapse, the heat shock protein (HSP) family plays a central role. ⁴ First discovered as stress-induced proteins, HSP family members are involved in cell defense mechanisms under stress conditions, aiding in preventing protein aggregation. ⁵ HSPs are divided into subfamilies based on molecular weight (Table 1), with Hsp90 and Hsp70 functioning as molecular chaperones and Hsp40 proteins acting as co-chaperones that modulate their ATPase activity and client specificity.^6-8

Table 1.

Function and Dysfunction of HSPs.

Protein family	Hps90	Hsp90	Hsp70	Hsp70	Hsp40
Protein/s of focus	Hsp90α (Hsp90aa1)	Hsp90β (Hsp90ab1)	Hsc70 (Hspa8)	Hsp70 (HSPA1A)	Auxilin, CSPα, DNAJ13
Molecular weight	90 kDa	90 kDa	70 kDa	70 kDa	40 kDa
expression in basal conditions	Basal level expression/stressed induced	Constitutively expressed	Constitutively expressed	Stress-induced	Constitutively expressed
Location in neurons	Dendrites, cytosol of soma, axons, synapse	Dendrites, cytosol of soma, axons, synapse	Dendrites, cytosol of soma, axons, synapse	Localized based on what stressful stimuli induced expression	Dendrites, cytosol of soma, axons, synapse
Synaptic localization	Post-synaptic density, pre-synaptic terminal	Post-synaptic density, pre-synaptic terminal	Pre-synaptic terminal, post-synaptic terminal	Localized based on what stressful stimuli induced expression	Pre-synaptic terminal, post-synaptic terminal
Synapse specific function	AMPA recycling, misfolded protein refolding, protein transport	AMPA recycling, misfolded protein refolding, protein transport	CME, AMPA endocytosis, misfolded protein refolding, synapsin transport	Activating HSF1 after a stress response and preventing misfolding of proteins	Co-chaperones that aid in the function of chaperones
Dysfunction in mental disorders	Linked to HPA axis 9	Linked to HPA axis 9	No direct human or PTSD/MDD studies, but known to be proteostasis guard and implicated in stress resilience	No currently published papers that link Hsp70 to PTSD/MDD	Dependent on HSP40 co-chaperone
	Significantly more research required	Significantly more research required	Significantly more research required		There are no direct links to Hsp40 and mental disorders yet, however the pathways that they influence have been linked to mental disorders
Dysfunction in neurodegenerative disorders	Upregulated 10	Upregulated 13	Upregulated 14	Upregulated 22	Dependent on HSP40 co-chaperone
	Inhibition linked to reduced tau pathology11,12	Inhibition linked to reduced tau pathology11,12	Partial inhibition reduces Tau pathology 15		CSP downregulated 16
					Auxilin loss of function mutations linked to PD 17
					DNAJC13 mutations linked to PD 18

Under normal conditions, HSP family members collaborate through dynamic interactions and form a chaperome to help maintain proper cellular functions.^19,20 At synapses, HSPs influence receptor trafficking, neurotransmitter release, synaptic plasticity, and are increasingly linked to mechanisms of resilience under pathological stress.^4,21,22 Recent findings suggest that dysfunction of the chaperome contributes not only to classical neurodegenerative pathologies, but also to psychiatric disorders where synaptic proteostasis is compromised.^19,23-25 These advances highlight the importance of reevaluating synaptic chaperone biology in neurological conditions. This minireview focuses on the interactions of Hsc70 (HSPA8), Hsp90α/β (HSP90AA1/HSP90AB1), and co-chaperones of the Hsp40/DNAJ family, emphasizing their roles in synaptic proteostasis, their dysfunction in disease, and their potential as therapeutic targets.

Section A

A1. General Functions of Hsp90/Hsc70/Hsp40

Hsp90 is highly abundant, comprising up to 2% of total cellular protein, and is known to interact with at least 300 client proteins across pathways including signal transduction, transcription, protein trafficking, protein degradation, protein folding and genomic stability.^26,27 The Hsp90 subfamily consists of two main isoforms, Hsp90aa1 (Hsp90α) and Hsp90ab1 (Hsp90β). These isoforms perform partially distinct functions during development and stress responses.^28,29 Hsp90aa1 has basal expression but is strongly stress-inducible, in contrast to the constitutive expression of Hsp90ab1. ²⁸ Hsp90aa1 is localized to the cytosol and can be excreted to the extracellular space in response to stress, referred to as eHsp90aa1.^29,30 eHsp90aa1 contributes to wound healing and cancer progression.^30,31 Hsp90ab1 is a housekeeping gene, with functions Hsp90aa1 cannot replace. ³² Hsp90ab1 is cytosolic, but in special cases can be excreted extracellularly such as in osteosarcoma cells (tumor cells). ³³

Hsc70 (HSPA8), is a constitutively expressed housekeeping member of the Hsp70 family and enriched in neuronal cells.^34-36 Due to the terms Hsp70 and Hsc70 being used interchangeably, it is crucial to distinguish them: Hsp70 (HSPA1A/B) is primarily stress-inducible, whereas Hsc70 (HSPA8) maintains basal proteostasis.^37,38 Hsp70 and Hsc70 distinct functions, but Hsc70 does aid Hsp70 in the stress response. ³⁹ Hsc70 is involved in multiple types of autophagy, ⁴⁰ clathrin-mediated endocytosis, ⁴¹ protein transport, ⁴² degradation, and folding.^43-45 Hsc70 activity is mainly driven by cochaperones and ATP hydrolysis; it oscillates between two states: an ATP-bound state and an ADP-bound state. ⁴⁶

The Hsp40 (DNAJ) family represents a large and functionally diverse class of co-chaperones that critically modulate Hsc70 activity. Their defining feature is the ∼70 amino acid J domain, which directly stimulates the ATPase activity of Hsc70 and recruits it to specific client proteins. ⁶ More than 40 DNAJ family members have been discovered, with several expressed in neurons and enriched at synaptic sites.^34,47,48 A defining feature of co-chaperones is their ability to impart functional specificity to otherwise broadly acting chaperones. ⁴⁹ Whereas Hsc70 alone possesses general ATP-driven folding activity, its outcome depends on the co-chaperone it engages. For example, Auxilin directs Hsc70 toward clathrin uncoating, thereby enabling vesicle recycling, while CHIP diverts Hsc70-bound clients toward degradation. Such divergence illustrates how the same core chaperone protein can be tuned to opposite outcomes, depending on its co-chaperone partners.

A2. Specific Functions of HSPs at the Synapse

As mentioned above, Hsp90aa1 and Hsp90ab1 have distinct roles. However, their individual contributions in the synapse are not completely characterized, which represents an important gap in our understanding of synaptic proteostasis (Table 1). In the brain, it is known that they exert different regulatory effects on opioid pain relief. ⁵⁰

At the synapse, Hsp90 regulates AMPA receptor recycling, ¹¹ synaptic plasticity, ⁵¹ and protein trafficking to mitochondria and peroxisomes. ⁵² Experimental evidence linking Hsp90 to these processes comes primarily from pharmacological inhibition and genetic perturbation studies. These studies show impaired long-term potentiation and altered receptor turnover following acute Hsp90 disruption, consistent with a requirement for dynamic chaperone cycling during synaptic plasticity.^53,54 Notably, chronic or partial inhibition of Hsp90 can yield divergent outcomes, including compensatory changes in receptor surface expression or synaptic strength, suggesting that the timing and magnitude of Hsp90 dysfunction critically influences synaptic phenotypes.^55,56

Hsp90 contributes to neurotransmitter release via interactions with α-Synuclein and Rab3a GTPase. Specifically, α-Synuclein binds to synaptic vesicles stabilizing SNARE proteins and preventing exocytosis of synaptic vesicles, with the help of a Rab3a GTPase (Figure 1a).^19,57-60 Hsp90 causes hydrolysis of GTP to GDP that is bound to Rab3a, causing disassociation of α-Synuclein from the synaptic vesicle, destabilizing the SNARE complex, increasing likelihood of the synaptic vesicle fusion.^19,51,60 These mechanisms are supported by biochemical and cell-based studies implicating chaperone regulation of Rab GTPase cycling and SNARE complex dynamics. However, some studies report context-dependent effects of α-synuclein on release probability, including both inhibitory and facilitatory roles depending on expression level and synaptic activity, underscoring the non-linear nature of chaperone-regulated vesicle fusion.^61,62

Figure 1.

Schematic diagrams of HSPs’ functions. (a) Hsp90 functions in vesicle exocytosis with SNARE proteins. (b) Hsc70 functions with CME in AMPA receptor recycling. (c) Hsc70/Hsp90 and co-chaperone HOP chaperome operate in refolding misfolded proteins or labeling misfolded proteins for degradation. (d) Hsc70 responds to stress in the synapse.

At synapses, Hsc70 performs essential functions maintaining the cytoskeleton structure of the synapse, ⁴ synapse vesicle recycling, ⁴¹ AMPA receptor recruitment, ⁶³ synapse proteostasis, ⁶⁴ synaptic transmission,^12,41 and protein transport. ⁴² These mechanisms have been demonstrated through genetic loss-of-function and dominant-negative approaches showing synaptic transmission defects and accumulation of endocytic intermediates when Hsc70 activity is compromised.^65,66

Hsc70 regulates synaptic vesicle endocytosis via the formation of clathrin coated vesicles (CCVs) and clathrin mediated endocytosis (CME) (Figure 1b). These CCVs need to be uncoated for their materials to be recycled. ⁶⁷ Clathrin mediated endocytosis is the process by which proteins are brought into the cytoplasm from the surface of the cell membrane. Hsc70 with co-chaperone Auxilin (a member of Hsp40 family) un-coats CCVs to releasing clathrin, thus making Hsc70 crucial for pre-synaptic terminal endocytosis. Auxilin is first targeted to clathrin because of its clathrin binding domain, Hsc70 then binds the J domain on auxilin. This stimulates the ATPase activity of Hsc70 allowing release of clathrin monomers from CCVs. ⁶⁷ This uncoating is regulated by CHl–1. ⁶⁷ These roles ensure continuous recycling of synaptic vesicles and sustain neurotransmission under high-demand conditions. While the mechanism for Hsc70–auxilin–mediated uncoating is well established, partial disruption of this machinery has been reported to produce heterogeneous synaptic outcomes, including synaptic depression or, in some activity states, transient increases in release probability. This reflects the tight coupling and balance between endocytosis and exocytosis during sustained neurotransmission.^66,67

Together, Hsp90 and Hsc70 establish a molecular backbone for synaptic resilience, maintaining synaptic proteostasis, balancing receptor trafficking, vesicle turnover, and cytoskeletal organization to preserve both basal activity and adaptive plasticity.

In the synapse, Hsp40 co-chaperones are not redundant; knockout or mutation of individual members often produces distinct synaptic phenotypes highlighting their specialized roles.^68,69 This specificity likely reflects a combination of unique structural domains,^70,71 subcellular localization, and activity-dependent regulation. The coexistence of multiple co-chaperones within the same neuron suggests that different co-chaperones compete or cooperate for Hsc70 binding, which may allow synapses to flexibly adjust to fluctuating physiological demands. As mentioned, only a few of the Hsp40 subfamily members are enriched in neuronal cells. Cysteine string protein and auxilin are the two subfamily members with the most neural related research completed.

The different cochaperone members of the Hsp40 family perform unique functions at the synapse. DNAJC5 (cysteine string protein, CSPα) and DNAJC6 (auxilin), play central roles in vesicle cycling through their interaction with Hsc70.^41,67,72,73 Auxilin (DNAJC6) is essential for clathrin-mediated endocytosis, where it recruits Hsc70 to clathrin-coated vesicles to promote uncoating and vesicle reuse.^24,67 CSPα (DNAJC5) interacts with Hsc70 and SNAP-25, stabilizing the SNARE complex and facilitating exocytosis of neurotransmitters into the synaptic cleft. ⁷² CSPα prevents presynaptic degeneration by facilitating exocytosis. ⁷⁴ DNAJC13, although less well characterized, is thought to regulate endocytic trafficking and contribute to synaptic vesicle recycling efficiency. ⁷³ The Hsp40 co-chaperones do not simply support Hsc70 function but direct it toward specific synaptic pathways that sustain neural transmission. More extensive research needs to be completed to further delineate the different functions these Hsp40 proteins perform at the synapse.

A3. Collaborative Chaperome Dynamics

Although Hsp90 and Hsc70 perform distinct functions, their cooperation as a chaperome complex is essential for maintaining proteostasis at the synapse. Both localize to dendrites, the postsynaptic density (PSD), and presynaptic terminals in basal conditions.^75-77 The Hsc70–Hsp90 chaperome is mediated by co-chaperones, particularly Hsp40/DNAJ proteins and the organizing protein HOP/STI1, which facilitates client transfer between Hsc70 and Hsp90.^44,78,79 Mechanistically, Hsc70 first recognizes and binds misfolded proteins in association with Hsp40. The Hsp40 cochaperone that contributes to this is dependent on the client protein that is being transferred. ⁸⁰ These substrates may either be targeted for degradation via ubiquitination or passed to Hsp90 through HOP for refolding (Figure 1c). ⁷ This chaperome complex is crucial for preventing toxic protein aggregation and sustaining synaptic proteostasis.

Interestingly, chaperome activity at the synapse extends beyond protein quality control. Hsc70 has been shown to recruit Hsp90 to the lysosomal membrane under pH-dependent conditions, suggesting roles in lipid or membrane remodeling that are still poorly understood. ⁸¹ This is important in its relation to neurodegeneration diseases because lipid dyshomeostasis has been linked to neurodegeneration. ⁸² This is a gap in our current knowledge and understanding of this chaperome complex.

These findings highlight that the Hsp70–Hsp90 chaperome is not a passive quality control system but an active regulator of synaptic proteostasis. By balancing refolding, degradation, and trafficking, this cooperative network enables synapses to withstand both proteotoxic and activity-driven stress.

Section B. Chaperome Dysfunction in Disease

B1: Epichaperome Formation

When the Hsc70/Hsp90 chaperome becomes dysfunctional, it is referred to as an “epichaperome”, which recruits additional co-chaperones normally not present in chaperomes. Even a few epichaperome forming in a cell can have significant negative effects on the cell as proteostasis in the cell is no longer maintained.^9,83-85 The exact mechanisms for epichaperome formation are not completely characterized, but chronic disease states and client overload are known triggers for epichaperome formation. ⁸⁴ There is evidence that post-translation modifications on Hsp90 stabilize the epichaperome formation by reducing cycling dynamics.^84,86 Chemical proteomic studies support a stepwise and cooperative transition into stable scaffolds, which can be pharmacologically dismantled, indicating conditional reversibility.^84,87,88 Together, these findings suggest a threshold-dependent network rewiring process rather than a single triggering event. By stabilizing normally dynamic chaperone interactions, epichaperomes bias substrate fate toward pathological retention, suppress signaling plasticity, and enforce persistent interaction networks.^84,87 This rigidity limits adaptive decision-making and potentially functions as a pathological checkpoint that locks cells into maladaptive proteostasis and signaling states. Pharmacologic dismantling of epichaperomes reverses these effects, supporting their role as network-level disease stabilizers rather than passive stress markers. ⁸⁷

This epichaperome formation has been researched in depth in different cancers, with a multitude of thorough reviews covering the topic.^85,89,90 It is known that epichaperomes contribute greatly to tumor survival and proliferation, performing several functions that facilitates tumor growth. ⁸⁴ In this minireview we focus on the role of epichaperomes in the synapse, specifically in relation to neurodegeneration and neuropsychiatric disorders. The role of the epichaperome in neuronal diseases is much different from its role in cancer.

B2. Stress and Disease-Relevant Roles at the Synapse

At the synapse, Hsp90 and Hsc70 not only safeguard proteostasis, but mediate adaptive responses to cellular stress. Under cellular stress, Hsc70 rapidly binds misfolded proteins and activates the transcription factor HSF-1, which in turn induces expression of stress-induced Hsp70 (HSPA1A).^37,38 Together they create a tiered defense, Hsc70 engages existing misfolded substrates, while newly transcribed Hsp70 provides an additional buffer against misfolding and aggregation (Figure 1d).

An interesting interaction occurs between Hsp90, Hsc70 and Hsp70 that needs to be further studied. As mentioned, Hsc70 binds HSF-1, leading to Hsp70 transcription. ⁴⁸ In contrast, inhibition of Hsp90 by preventing it from binding to HSF-1 leads to upregulation of Hsp70.^5,91 There have already been clinical trials using Hsp90 inhibition to increase Hsp70, which leads to better outcomes for neurodegeneration.^20,26,91,92 Both Hsp90 and Hsc70 being upregulated after a stressor are somewhat confusing, because Hsp90 and Hsc70 display opposite regulatory effects on HSF-1.^9,93 Hsp90 sequesters HSF-1 activity, while Hsc70 promotes HSF-1 activity. The prevention of Hsp90 binding to HSF-1 would potentially allow Hsc70 to bind to HSF-1. ³⁹ This pathway is of interest because of its involvement in protein misfolding and the impact on neurodegenerative diseases and other brain disorders.^83,92 In the future, understanding how their interaction affects synapses during a stress response or in a disease state could lead to a better understanding of how to treat brain disorders.

When stress persists, dysregulation of the chaperome can tip toward pathological states. Upregulated Hsp90 has been linked to tau aggregation and toxic proteostasis collapse in Alzheimer’s disease, ²⁰ while impaired Hsc70 function disrupts clathrin-mediated endocytosis and AMPA receptor recycling, weakening synaptic transmission. ⁶³ Formation of the epichaperome represents a maladaptive remodeling of the Hsp70/Hsp90 network, where chaperones become locked into dysfunctional complexes that propagate synaptic stress.^83,84 If excess aggregation occurs, Hsc70 and Hsp90 will be recruited to process misfolded proteins, and other functions that Hsp90 and Hsc70 are involved in will be affected.^43,44,79

This evidence further suggests that these stress-regulated dynamics extend beyond neurodegenerative diseases to psychiatric disorders, where chaperome dysfunction undermines synaptic resilience.^9,14,15 This broadens the relevance of chaperome biology, positioning Hsp90 and Hsc70 as central regulators of both neuronal stress tolerance and disease vulnerability.

B3. Alzheimer’s Disease and Tau/Aβ Pathology

The involvement of Hsc70 and Hsp90 in Alzheimer’s disease (AD) has been investigated with mixed results.^4,20,94-96 Both β-amyloid (Aβ) deposition and tau aggregation have been shown to interact with these chaperone systems. Partial inhibition of Hsc70 reduces tau pathology in mouse models, whereas complete inhibition leads to accumulation of tau and other toxic aggregates. ⁴ The inhibition of Hsp90 has been shown to reduce tauopathy and improve AD pathologies in mouse models.^19,20 It is hypothesized that inhibition of Hsp90 improves tauopathy and Abeta pathology by activating or increasing the expression of Hsp70 and Hsc70. Hsp70 and Hsc70 are part of the stress response that targets misfolded proteins and aggregates, that could be defensive against AD pathology. However, there are studies in C.elegans suggesting that Hsp90 inhibition can be neurotoxic and worsen AD relevant pathologies.^92,97 These experiments were repeated in 5xFAD, mice models of AD. While Hsp90 up-regulation is protective against Abeta plaques in C.elegans, in 5xFAD mice the upregulation of Hsp90 leads to an increase of Abeta plaques. ⁹⁷ These inconsistencies underscore the context dependence of chaperone modulation; there are differences among species and the balance of Hsp90 versus Hsc70 activity may explain divergent outcomes.

Under normal conditions the Hsp90/Hsc70/Hop chaperome blocks Tau aggregation. If the dynamics of this chaperome are disrupted, accumulation of Tau occurs.^98,99 Epichaperome formation has been shown to happen prior to tau pathology in mice. ⁸⁸ This highlights the importance of healthy chaperome dynamics to prevent AD pathology. There is no evidence of extracellular epichaperomes in current research, meaning that Abeta has no direct interactions with epichaperomes. Therefore, it can be hypothesized that epichaperome formation in AD is compartment-restricted, with pathological consequences emerging predominantly in intracellular tau-associated networks rather than extracellular Abeta assemblies. One emerging mechanism is that during AD progression, Hsc70 and Hsp90 are recruited away from their synaptic proteostasis functions to target accumulating tau aggregates, inadvertently contributing to loss of synaptic proteostasis.^{43,44,79,100,101}

B4. Parkinson’s Disease and α-Synuclein Aggregation

Increasing evidence indicates that these molecular chaperones play roles in the pathogenesis of Parkinson’s disease (PD).^{64,95,102,103} The aggregation of α-synuclein (α-Syn) is associated with PD, and Hsc70 has been found to have a higher binding affinity for α-Syn aggregates versus soluble α-Syn. ⁶⁴ The Hsc70 coated α-Syn aggregates were shown to be less toxic than the aggregates that were not coated with Hsc70, suggesting that it plays a part in PD pathology. ⁶⁴ Additionally, Hsp90 is associated with α-Syn, and in Parkinson’s patients, both Hsp90 and α-Syn have been found to be colocalized. ¹⁰⁴ The inhibition of Hsp90 can be protective in the dopamine cell death observed in PD. ¹⁰² The involvement of Hsp90 and Hsc70 dysregulation in neurodegenerative disorders highlights their importance for synapse maintenance.

Collectively, these findings suggest that Hsc70 can act as a detoxifying coat on α-synuclein aggregates, while Hsp90 may determine whether α-synuclein clients are directed toward refolding or aggregation. However, as in AD, results vary depending on the degree and timing of chaperone modulation, again raising the possibility that disease pathology exploits the same proteins that normally stabilize synaptic proteostasis.

B5. Psychiatric Disorders: Stress, Depression, and PTSD

Beyond classical neurodegenerative disorders, there is growing evidence that Hsp90 and Hsc70 are involved in psychiatric illnesses, where loss of synaptic proteostasis rather than cell death is the critical endpoint.^105-108 Both chaperones influence proteins central to mood regulation, including the vesicular monoamine transporter VMAT2, which packages dopamine and serotonin into vesicles^109,110 and AMPA-type glutamate receptors, whose trafficking is tightly linked to plasticity in depression and stress.^111,112 HPA axis dysregulation is another common biological factor in patients with PTSD and major depressive disorder. ¹¹³ Hsp90 is linked to the HPA axis through the glucocorticoid receptor. Hsp90 regulates glucocorticoid receptor, maintaining HPA axis homeostasis. ¹⁷

In PTSD, chronic stress is associated with an influx of misfolded proteins and sustained upregulation of Hsp90 and Hsc70. ¹⁰⁶ A plausible mechanism is that chaperones target the influx of misfolded proteins, leading to the creation of stress-induced chaperome assemblies and diminishing their availability for baseline synaptic tasks such as AMPA receptor recycling or clathrin-mediated endocytosis. This loss of synaptic proteostasis could lead to long-term depression of synaptic strength and eventual connectivity loss, both hallmarks of stress-related disorders. Depression and schizophrenia may similarly reflect imbalances in chaperone availability versus synaptic demand, although these mechanisms remain unknown and the mechanism mentioned above is hypothesized. There is a lack of research exploring chaperones and their impact on psychiatric diseases, representing a gap in the current understanding of how these chaperones function in psychiatric diseases.

B6. A Cross-Disease Perspective

Under normal conditions, Hsp90 and Hsc70 form the backbone of synaptic proteostasis, coordinating distinct but interdependent functions. Hsp90aa1 and Hsp90ab1 regulate receptor trafficking, neurotransmitter release, and activity-dependent plasticity, while Hsc70 (Hspa8) ensures efficient vesicle recycling, AMPA receptor turnover, and rapid responses to proteotoxic stress. These proteins often converge through the formation of a chaperome, stabilized by Hsp40 co-chaperones and the Hsp70/Hsp90 organizing protein (HOP). Within this network, Hsc70 typically identifies misfolded substrates and either directs them toward degradation or transfers them to Hsp90 for refolding (Figure 2a).

Figure 2.

Schematic diagram of Hsp90 and Hsc70 in healthy and diseased synapses. (a) Hsp90 and Hsc70 display balanced functions in health synapses. (b) Hsp90 and HSc70 display imbalance functions in diseased states or after continuous stress.

When balanced, this collaboration maintains synaptic resilience across fluctuating demands. However, under chronic stress or disease, chaperome dynamics can become maladaptive, as seen in epichaperome formation, where stable but dysfunctional complexes accumulate and propagate synaptic failure. This positions Hsp90 and Hsc70 interactions as a central hub in determining synaptic fate.

Neurodegenerative and neuropsychiatric conditions appear to share a common theme: when chaperone systems are diverted toward pathological aggregates or stress responses, synaptic proteostasis is compromised. At present, no direct link has been identified between epichaperome formation and PTSD; however, such a link exists in AD. Because both PTSD and AD exhibit an influx of misfolded proteins, a potential mechanistic link between the two may involve Hsc70 and Hsp90 being diverted away from synaptic proteostasis functions to target misfolded proteins. When these proteins are diverted away from baseline functions this ultimately leads to loss of proteostasis in the synapsis (Figure 2b). This could also be affected by epichaperome formation. While this has been established in AD, it requires further investigation for PTSD and other neuropsychiatric disorders. Hsc70 and Hsp90 can be either protective or maladaptive depending on the context, co-chaperone availability, and disease stage. This framework suggests that therapeutic approaches targeting the chaperome must be highly selective—enhancing beneficial interactions while avoiding disruption of synaptic function.

Although epichaperomes share a conserved core chaperone architecture across diseases, their composition and network topology differ markedly by context. In cancer, epichaperomes are enriched in signaling and cell-cycle regulators, forming dense networks that stabilize oncogenic signaling.^84,86,88 In neurodegenerative diseases, they preferentially associate with synaptic, cytoskeletal, and RNA-binding proteins, reinforcing rigid, dysfunctional neuronal states.^84,88,97 These differences reflect convergence on a shared proteostasis failure, driven by distinct chronic stressors, resulting in disease-specific pathological outcomes. Together, these observations raise the possibility that epichaperomes encode not only survival or degenerative states, but also persistent maladaptive plasticity states, expanding their relevance to psychiatric diseases. Psychiatric disorders may represent a third distinct context for epichaperome formation, driven by chronic psychosocial stress rather than oncogenic signaling or overt proteotoxic aggregation. In this context, epichaperome assemblies would be predicted to stabilize synaptic stress-responsive signaling networks, enforcing maladaptive plasticity states without triggering degeneration. Such a configuration could act to constrain network flexibility and contribute to the persistence of psychiatric symptoms despite the absence of irreversible cellular damage. However, many more experiments need to be performed before conclusions surrounding epichaperomes and psychiatric disorders can be drawn.

Discussion and Future Directions

Hsc70 and Hsp90aa/ab emerge as central regulators of synaptic proteostasis, operating at the interface of receptor trafficking, vesicle cycling, and stress adaptation. Together with their co-chaperones, these proteins form a dynamic chaperome that safeguards synaptic function under basal conditions while also responding to proteotoxic insults. The evidence presented here suggests that when these systems are balanced, they enable efficient neurotransmission and plasticity; when dysregulated, they contribute to vulnerability across both neurodegenerative and psychiatric contexts.

A unifying theme is that the same chaperone activities that defend against aggregation can paradoxically destabilize synaptic function if they become over-recruited. In Alzheimer’s and Parkinson’s models, Hsc70 and Hsp90 are redirected toward toxic protein assemblies, leaving fewer resources for baseline synaptic tasks such as AMPA receptor recycling or clathrin-mediated endocytosis. A similar diversion may occur in psychiatric disorders such as PTSD or depression, where chronic stress increases misfolded protein burden and chaperome activity. This cross-disease perspective reframes synaptic chaperones not as disorder-specific factors, but as shared nodes of vulnerability and resilience across brain disorders.

Conceptual advances over the last five years have sharpened this view. The epichaperome model highlights how maladaptive chaperone networks can form under chronic stress, amplifying dysfunction beyond individual HSPs. Structural studies have clarified how Hsp40 family members direct Hsc70 and Hsp90 toward distinct fates, offering a partial explanation for the contradictory results seen across model systems. Nevertheless, questions remain, particularly regarding species differences, functional redundancy among family members, and the extent to which stress-induced remodeling versus constitutive roles dominate in disease states.

Taken together, this leaves the question of whether these HSPs have therapeutic potential. Hsp90 and Hsc70 interact with many client proteins, targeting them without unintended effects on pathways unrelated to the disease is challenging. Hsp90 inhibition could lead to improved Abeta pathologies in humans as it did mouse models, ⁹² but further experiments need to be performed. However, the therapeutic inhibitor must cross the blood-brain-barrier and Hsp90 inhibition itself influences the blood-brain-barrier integrity. ¹¹⁴ Due to the wide range of pathways Hsp90 and Hsc70 regulate, targeting a Hsp40 co-chaperone or HOP could be practical. This has its own challenges, as HOP and Hsp40 co-chaperones are expressed in a magnitude of cell types. Finding a way to manipulate these proteins expression exclusively at the synapse could be beneficial for both neurogenerative and neuropsychiatric disorders.

There are still many limitations to the research surrounding these proteins, as many of these studies have been conducted in mouse models and cell cultures. Both these methods do not precisely represent how the HSP family members act in human neurons. Their functions in different neuron cell types still need to be fully characterized. There are limited studies on Hsc70, Hsp90, and Hsp40 involvement in neuropsychiatric disorders, making it more difficult to establish them as a definitive cross-disease biomarker between neuropsychiatric and neurodegenerative disorders. However further research into this link between these two disorders could prove fruitful.

Several open questions remain about co-chaperone selectivity in neurons, which is important to answer for future understanding of brain disorders. One key uncertainty is how Hsc70 distinguishes among its many potential co-chaperone partners. Structural motifs within the J domain provide some clues, but local protein environments and activity states also contribute.

Another unresolved issue is the division of labor among DNAJCs, while some preferentially act presynaptic (eg, auxilin, CSPα), others influence postsynaptic or trafficking pathways. Similarly, the degree to which co-chaperone expression varies across neuronal subtypes, developmental stages, or activity states is not yet fully understood.

Future work combining single-cell transcriptomics, proteomic mapping, and live-cell imaging of chaperone–co-chaperone complexes will be essential to address these questions. Such approaches could reveal whether co-chaperones act in mutually exclusive modules or dynamically exchange roles, shedding light on how synapses exploit this molecular diversity to maintain resilience.

Conclusion

Several open questions stand out: How do different DNAJC co-chaperones achieve specificity at the synapse, and what determines whether a misfolded protein is refolded versus degraded? To what degree can Hsc70/Hsp90 activity be pharmacologically tuned without impairing essential baseline functions? Can interventions targeting the chaperome achieve enough synaptic precision to be clinically viable? These questions highlight the need for more integrative approaches that combine structural biology, circuit-level analyses, and human genetics.

Hsc70 and Hsp90, together with their co-chaperones, should be viewed not only as stress proteins but as active participants in maintaining synaptic resilience. Their dual roles in health and disease highlight both the opportunities and challenges of therapeutic targeting. As research continues to bridge neurodegeneration and psychiatry, synaptic chaperone biology may emerge as a unifying framework for understanding brain disorders.