bims-proned 2026-10-04 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–10–04
fourteen papers selected by
Verena Kohler, Umeå University

Proteostasis (in)action: the role of co-pathologies in neurodegenerative disease.
Cellular and systemic modifiers of alpha-synuclein proteostasis.
Differential proteostasis imbalance and the molecular basis of distinct synucleinopathies and tauopathies.
From aggregate structure to disease trajectory: the role of the proteostasis network.
The microbiota-proteostasis axis: implications in neurodegenerative diseases.
Neuroinflammation and Autophagy in Neurodegeneration: Cellular Mechanisms and Therapeutic Strategies.
Dual effect of α-synuclein disease variants on condensate formation.
Hyphenated Mass Spectrometry-Based Strategies for Characterizing Oligomers of α‑Synuclein in Parkinson's Disease.
A water-pinning hotspot drives templated tau aggregation.
Astrocytic cathepsin D promotes α-synuclein processing and Lewy neurite-like aggregate maturation.
Polyamines across neurodegenerative proteinopathies.
Chaperone-mediated remodelling of mutant huntingtin.
LRSAM1, an E3 ubiquitin ligase, modulates TDP-43 proteostasis in amyotrophic lateral sclerosis.
Protein rheostasis: quality control in metastable proteomes.

Philos Trans R Soc Lond B Biol Sci. 2026 Oct 01. pii: 20250273. [Epub ahead of print]381(1960):

Proteostasis (in)action: the role of co-pathologies in neurodegenerative disease.

James F Morley.

  Clinically distinct neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), share in common progressive neuronal dysfunction and cell death associated with the accumulation of misfolded proteins. Central to these processes are the cellular and organismal proteostasis networks responsible for maintaining protein homeostasis through coordinated actions of molecular chaperones, the ubiquitin-proteasome system and autophagy-lysosomal pathways. As a consequence of ageing, genetic modifications and other disease-specific conditions, the proteostatic network becomes compromised, leading to the accumulation of toxic protein aggregates that disrupt neuronal function and lead to neurodegeneration. Specific misfolded proteins are associated with each neurodegenerative disease (i.e. α-synuclein in PD, amyloid-β/tau in AD and TAR DNA-binding protein 43/SOD in ALS). However, increasing evidence implicates more complex interactions of co-pathologies across these disorders, as Lewy bodies are common in AD brains and Alzheimer pathology is present in the majority of PD autopsy cases. These observations are consistent with the idea that disruption of proteostasis networks by one aggregation-prone protein could result in misfolding and aggregation of other neurodegeneration-related species. This review will examine the characteristics and consequences of co-pathologies in neurodegenerative disorders. Additionally, the review will outline emerging therapeutic strategies targeted at restoring proteostasis and mitigating the effects of co-pathological processes associated with neurodegenerative diseases. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.

Keywords:  co-pathology; neurodegeneration; proteostasis

DOI:  https://doi.org/10.1098/rstb.2025.0273
Philos Trans R Soc Lond B Biol Sci. 2026 Oct 01. pii: 20250275. [Epub ahead of print]381(1960):

Cellular and systemic modifiers of alpha-synuclein proteostasis.

Suzanne Couzijn, Anna P Ainslie, Alejandro Herron-Bedoya, Ellen A A Nollen.

  Ageing is a primary risk factor for neurodegenerative disorders, including Parkinson's disease (PD). As individuals age, their cells become less efficient in maintaining protein homeostasis, leading to an increased likelihood of protein misfolding and aggregation. A hallmark of PD and other synucleinopathies is the accumulation of alpha-synuclein protein aggregates in affected neurons, a process that is exacerbated by ageing. While cellular mechanisms that regulate protein aggregation have been a primary focus of research, recent studies suggest that other, systemic age-related mechanisms may contribute to alpha-synuclein toxicity. Understanding these alternative pathways is crucial for the development of effective therapeutic strategies to combat neurodegenerative diseases, such as PD. In this review, we synthesize current insights into the biological mechanisms underlying alpha-synuclein toxicity at the organismal level. We highlight key open questions and discuss how these findings may inform the development of targeted interventions to prevent or delay age-related synucleinopathies. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.

Keywords:  ageing; alpha-synuclein; protein aggregation; protein condensation; proteostasis

DOI:  https://doi.org/10.1098/rstb.2025.0275
Philos Trans R Soc Lond B Biol Sci. 2026 Oct 01. pii: 20250272. [Epub ahead of print]381(1960):

Differential proteostasis imbalance and the molecular basis of distinct synucleinopathies and tauopathies.

Virginie Redeker, Ronald Melki.

  This short review discusses the structural and molecular events at the origin of diverse debilitating neurodegenerative diseases. The pathological consequences owing to the primary, secondary, tertiary and quaternary structural diversity of alpha-synuclein and tau proteins and the aggregates they form are presented. The crosstalk between alpha-synuclein and tau proteins aggregates structural heterogeneity and cellular homeostasis, and more precisely the proteostasis network is next considered. Overall, the proteostasis network appears as the master regulator of distinct synucleinopathies and tauopathies progression depending on its capacity to clear and/or disassemble to completion structurally diverse alpha-synuclein or tau fibrillar aggregates or not. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.

Keywords:  Alzheimer's disease; Parkinson's disease; alpha-synuclein; interactome; neurodegenerative diseases; protein folding and aggregation; protein–protein interaction; proteostasis; structural diversity; tau

DOI:  https://doi.org/10.1098/rstb.2025.0272
Philos Trans R Soc Lond B Biol Sci. 2026 Oct 01. pii: 20250276. [Epub ahead of print]381(1960):

From aggregate structure to disease trajectory: the role of the proteostasis network.

Jessica Tittelmeier, Carmen Nussbaum-Krammer.

  Neurodegenerative diseases are characterized by the accumulation of a small number of misfolded proteins, yet they differ markedly in cellular vulnerability and clinical outcome. We propose that this heterogeneity arises from the interaction between two largely orthogonal variables: the structural identities of protein aggregates and the identities of the cellular proteostasis networks (PNs) that engage them. Protein aggregates exist as structurally diverse assemblies with distinct intrinsic properties. At the same time, PNs vary between cell types, disease states and ageing in their composition, capacity and plasticity. As a result, the same aggregate can be efficiently cleared in one cellular context but persist, be remodelled, or give rise to self-propagating species in another. Likewise, the same PN can be protective or harmful, depending on the aggregate it encounters. Because neither aggregates nor PNs are static, their interaction evolves over time, leading to dynamic feedback between aggregate identity and PN state that shapes disease onset, progression and clinical symptoms. This view reframes neurodegenerative disease as a failure of compatibility between specific aggregate structures and the cellular protein quality control network that processes them rather than as a uniform collapse of proteostasis, and provides a framework for understanding selective vulnerability and disease trajectories. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.

Keywords:  chaperones; neurodegenerative diseases; prion-like propagation; protein aggregation; protein disaggregation; protein quality control; proteostasis network; structural polymorphs

DOI:  https://doi.org/10.1098/rstb.2025.0276
Philos Trans R Soc Lond B Biol Sci. 2026 Oct 01. pii: 20250265. [Epub ahead of print]381(1960):

The microbiota-proteostasis axis: implications in neurodegenerative diseases.

Daniel M Czyż, Brittani M Brown.

  Disruption of protein homoeostasis, or proteostasis, is a hallmark of protein conformational diseases (PCDs), including Alzheimer's and Parkinson's disease. These disorders are characterized by progressive protein aggregation and cellular dysfunction, yet no effective therapies exist. Emerging evidence indicates that microbial communities influence host proteostasis, giving rise to the concept of the microbiota-proteostasis axis. Microbes and their products can modulate host proteins by engaging with host proteostasis. As such, microbial dysbiosis has been linked to proteostasis disruption through the production of metabolites, extracellular vesicles, functional amyloids, and toxins or effector proteins capable of seeding or destabilizing host proteins associated with PCDs. These microbial factors have been shown in experimental models to converge on key proteostasis pathways, including protein synthesis, folding and clearance, thereby potentially reducing cellular buffering capacity and lowering the threshold for proteotoxic collapse. In parallel, microbiota-driven influence on inflammatory responses and immune signalling further amplifies systemic proteostasis disruption. In this review, we synthesize emerging evidence defining the microbiota-proteostasis axis and highlight how microbial factors influence host proteostasis. Importantly, these host-microbe interactions often precede neurodegeneration, suggesting potential for early detection and intervention. Together, these insights support targeting the microbiota as a potential strategy to enhance proteostasis and delay or prevent neurodegenerative disease. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.

Keywords:  Alzheimer's disease; Parkinson's disease; bacteria; gut–brain axis; microbiota; microbiota–proteostasis axis; neurodegenerative diseases; proteostasis

DOI:  https://doi.org/10.1098/rstb.2025.0265
CNS Neurol Disord Drug Targets. 2026 Sep 29.

Neuroinflammation and Autophagy in Neurodegeneration: Cellular Mechanisms and Therapeutic Strategies.

Anushka Verma, Swatantra Kumar Singh Kushwaha, Neelottama Kushwaha, Sayantan Dutta, Parul Nigam.

  Neurodegenerative diseases, including Huntington's disease, Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal dysfunction and loss, often accompanied by toxic protein aggregation and chronic neuroinflammation. Increasing evidence indicates that dysregulated autophagy and persistent inflammatory responses are central drivers of disease onset and progression. Autophagy, a fundamental cellular degradation and recycling process, is essential for maintaining neuronal homeostasis by removing damaged organelles and misfolded proteins through mechanisms such as macroautophagy and mitophagy. However, key regulators of this pathway, including ULK1, Beclin-1, LC3, and p62/SQSTM1, are frequently impaired in neurodegenerative conditions, leading to the accumulation of pathogenic proteins such as tau, α-synuclein, and amyloid-β. Concurrently, aberrant activation of microglia and inflammasomes promotes the sustained release of pro-inflammatory cytokines, creating a neurotoxic environment that exacerbates neuronal injury. This review examines the molecular crosstalk between autophagy and neuroinflammation, with particular emphasis on disease-specific mechanisms, including LC3-associated endocytosis (LANDO) in Alzheimer's disease, tau-mediated pathology, and dopaminergic neurodegeneration in Parkinson's disease. Importantly, this review introduces a unifying conceptual framework in which neuroinflammation and autophagy are integrated as a dynamic, stagedependent immune-autophagy axis that governs neurodegenerative disease progression and therapeutic responsiveness. In addition, emerging multimodal therapeutic strategies targeting both autophagic flux and immune modulation are discussed, including mTOR inhibitors, mitophagy enhancers, GLP-1 receptor agonists, and nanomedicine-based delivery systems. Advances in three-dimensional organoids, induced Pluripotent Stem Cell (iPSC) models, and biomarker-driven clinical trials are further enhancing translational potential. In conclusion, understanding the interplay between autophagy and neuroinflammation provides critical insights into the pathophysiology of neurodegeneration and offers promising avenues for the development of targeted, disease-modifying therapies.

Keywords:  Neuroinflammatory; autophagy; neurodegeneration; pathology.; receptors; therapeutic strategies

DOI:  https://doi.org/10.2174/0118715273459017260922073618
Nat Commun. 2026 09 02. pii: 10442. [Epub ahead of print]17(1):

Dual effect of α-synuclein disease variants on condensate formation.

Aswathy Chandran, Aishwarya Agarwal, Tianhao Wang, Leslie Amaral, Shiyue Chen, Susana R Chaves, Tiago F Outeiro, Janin Lautenschläger.

α-synuclein is a pre-synaptic protein implicated in synucleinopathies including Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies, where it accumulates in intracellular aggregates termed Lewy bodies and Lewy neurites. Recent studies have reported that α-synuclein undergoes phase separation to form biomolecular condensates both in vitro and in mammalian cells. α-synuclein condensates are thought to contribute to disease through progressive aggregation. Here we show that specific PD-associated α-synuclein variants fail to form biomolecular condensates. We demonstrate that only two α-synuclein variants associated with disease, E46K and E83Q, enhance condensate formation. While other α-synuclein disease variants including A30G, G51D, and A53E fail to form condensates in cells. In iPSC-derived neurons, the extent of synaptic enrichment of different α-synuclein variants is linked to their propensity to undergo VAMP2-mediated phase separation. Our results emphasize that α-synuclein dysfunction may follow divergent pathways, with both increased and decreased condensate formation.

DOI: https://doi.org/10.1038/s41467-026-77002-4
ACS Cent Sci. 2026 Sep 23. 12(9): 1360-1371

Hyphenated Mass Spectrometry-Based Strategies for Characterizing Oligomers of α‑Synuclein in Parkinson's Disease.

Raya Sadighi, Andrea Istrati, Sigourney Karijodikoro, Guus Scheefhals, Melissa Baerenfaenger, Anouk M Rijs.

The pathological aggregation of α-synuclein (α-syn), an intrinsically disordered protein that regulates synaptic vesicle trafficking in the brain, is a defining molecular feature in Parkinson's disease (PD). Early oligomeric assemblies are widely considered the most neurotoxic species, yet their structural features remain unexplored due to their low abundance, transient, and fragile nature. Here, we establish a trapped ion mobility-mass spectrometry (TIMS-MS) strategy that enables direct detection and structural interrogation of these oligomers. Low-flow size exclusion chromatography provides MS-compatible desalting and reveals broad ensemble-level differences between fresh and aggregated α-syn. Native TIMS-MS measurements uniquely probe numerous higher-order oligomers, thereby revealing a reduced conformational heterogeneity with increasing oligomer size, supporting a linear β-strand-type assembly pathway. These findings show that oligomerization drives a transition from dynamic monomers to increasingly ordered intermediates. This progressive rigidification is relevant to models in which α-syn oligomerization alters normal membrane engagement during PD-associated aggregation.

DOI: https://doi.org/10.1021/acscentsci.6c00514
bioRxiv. 2026 Sep 24. pii: 2026.08.04.742883. [Epub ahead of print]

A water-pinning hotspot drives templated tau aggregation.

Chung-Ta Han, Karen Tsay, Samuel Lobo, Saeed Najafi, Kieran Monahan, Erica Hong, M Scott Shell, Joan-Emma Shea, Songi Han.

Tau assembles into fibrillar aggregates that are pathological hallmarks of a group of neurodegenerative diseases collectively called tauopathies. Templated aggregation of naïve tau to seeding-competent fibrils that proceed from cell to cell is a key driver of prion-like progression of tauopathies. This study tests the hypothesis that tau, an intrinsically disordered protein (IDP), achieves in-register stacking to form seed-competent fibrils by a pinning action of tau to each other and/or the seed surface via a single dominant hotspot to avoid mismatch in tau stacking to fibrils. Structured solvation water has been proposed to be a signature of such hotspots at both the tau fibril-end surface and soluble tau monomers. Although jR2R3-P301L tau exhibits a heterogeneous hydration landscape in its intrinsically disordered state, with enhanced water structuring near the P301L mutation site, it is unclear whether a localized hotspot exists at the fibril end surface and surface water facilitates the initial contacts in templated aggregation. Using rapid 1H-15N SOFAST-HMQC NMR to track seed-induced aggregation of jR2R3-P301L in real time, complemented by molecular dynamics simulation of fibril surface hydration, we identify a residue-specific pinning hotspot that is prone to dewetting followed by sequential folding and incorporation of the remaining segment in a two-step dock-and-lock process. Site-specific spin labeling further demonstrates that blocking this pinning hotspot disrupts templated aggregation, leading to shorter fibrils. The identification of a dominant pinning site will facilitate the rational design of binders to effectively disrupt fibril extension or serve as diagnostic or therapeutic strategies.

DOI: https://doi.org/10.64898/2026.08.04.742883
EMBO Rep. 2026 Oct 02.

Astrocytic cathepsin D promotes α-synuclein processing and Lewy neurite-like aggregate maturation.

Hiroshi Hanafusa, Kota Ohashi, Hiromu Shojima, Yurika Honda, Naoki Hisamoto, Takeshi Kameyama, Muneaki Miyata, Kiyohito Mizutani, Yoshimi Takai, Kunihiro Matsumoto.

Parkinson's disease (PD) and related synucleinopathies are marked by the accumulation and propagation of α-synuclein (α-syn) aggregates, a process primarily studied in neurons. Whether astrocytes actively contribute to α-syn processing and intercellular transfer remains unclear. Here, using a physiologically relevant neuron-astrocyte co-culture system that recapitulates tripartite synapse architecture, we show that astrocytes process α-syn and influence the morphological maturation of neuronal aggregates. Astrocytes internalize α-syn pre-formed fibrils (PFFs) and generate C-terminally truncated α-syn species via a Cathepsin D (CtsD)-dependent process. PFF-loaded astrocytes transfer α-syn-containing material to neurons and promote the formation and maturation of pS129-α-syn-positive Lewy neurite (LN)-like aggregates. Notably, α-syn PFF exposure induces lysosomal membrane damage, a senescence-like reactive state, and CtsD upregulation in astrocytes. Although PFF-containing lysosomes undergo autophagic engulfment, they persist within astrocytes, and a subset is detected beyond the astrocytic membrane boundary. Together, our findings support a model in which astrocytic lysosomal remodeling of internalized α-syn contributes to the morphological maturation and intercellular propagation of neuronal α-syn pathology in this co-culture system.

DOI: https://doi.org/10.1038/s44319-026-00927-w
Neurobiol Dis. 2026 Sep 26. pii: S0969-9961(26)00375-X. [Epub ahead of print]230 107629

Polyamines across neurodegenerative proteinopathies.

Bedri Ranxhi, Peter A LeWitt, Wei-Ling Tsou, Sokol V Todi.

  Polyamines (PAs) are evolutionarily conserved metabolites that connect protein quality control with lysosomal, mitochondrial, and redox homeostasis. Their metabolism is situated at a critical intersection of cell-sustaining and neurodegenerative pathways. Here, we synthesize evidence across Alzheimer's disease, Parkinson's disease, polyglutamine repeat disorders, amyotrophic lateral sclerosis, and multiple system atrophy, each of which differs in vulnerability to changes in PA metabolism. Although previous reviews have investigated PAs in individual neurodegenerative disorders, few have compared their roles across the broader spectrum of neurodegenerative proteinopathies. We address this gap by synthesizing evidence across multiple diseases to examine how PAs influence disease-associated protein aggregation and clearance, and how these effects depend on PA species, concentration, cellular context, disease stage, subcellular localization, redox state, and lysosomal and mitochondrial capacity. Human tissue and biofluid studies report disease-associated changes in PA metabolites, pathway enzymes, and transporter remodeling, as a function of neurodegenerative disorders. Mechanistic studies reveal that spermidine and spermine can alter the assembly, condensation, compartmentalization, and clearance of various neurotoxic proteins, whereas the effects of putrescine are more system- and concentration-dependent. These effects engage both shared pathways and distinct mechanisms, depending on protein identity, cell type, and subcellular location. Curiously, PA manipulation may be protective in one context yet harmful in another. The framework that we propose can distinguish adaptive remodeling from pathogenic dysregulation and can guide disease-relevant therapeutic strategies.

Keywords:  Aggregation; Alzheimer’s; Amyotrophic lateral sclerosis; Autophagy; Mitochondria; Multiple system atrophy; Oxidative stress; Parkinson’s; Polyglutamine; Proteostasis; Spermidine; Spermine; Synucleinopathies

DOI:  https://doi.org/10.1016/j.nbd.2026.107629
Philos Trans R Soc Lond B Biol Sci. 2026 Oct 01. pii: 20250269. [Epub ahead of print]381(1960):

Chaperone-mediated remodelling of mutant huntingtin.

Kunal Gharat, Janine Kirstein.

  Huntington's disease is caused by the trinucleotide repeat CAG expansion in the huntingtin gene, resulting in an N-terminal polyglutamine (polyQ) tract that renders the huntingtin protein (HTT) prone to misfolding and aggregation. Although polyQ expansion is an intrinsic driver of aggregation, the folding trajectory of HTT is strongly shaped by molecular chaperones that detect all conformational entities of HTT and as such bind to soluble HTT and suppress β-sheet formation, target HTT for proteasomal degradation and resolubilize HTT fibrils by disaggregation. This review summarizes recent in vitro and in vivo data on the role of molecular chaperones in the HTTExon1 folding landscape and its cooperation with the proteolytic pathways. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.

Keywords:  chaperones; huntingtin; proteostasis

DOI:  https://doi.org/10.1098/rstb.2025.0269
Brain. 2026 Sep 28. pii: awag334. [Epub ahead of print]

LRSAM1, an E3 ubiquitin ligase, modulates TDP-43 proteostasis in amyotrophic lateral sclerosis.

Takayuki Shirakawa, Satsuki Mikuriya, Yuki Inoue, Kota Murasaki, Florencia Salinas, Tomo Takegawa-Araki, Makoto Tamura.

  Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by the cytoplasmic mislocalization, aberrant phosphorylation and pathological aggregation of TDP-43, a nuclear RNA-binding protein essential for RNA metabolism. Despite its central involvement in ALS pathogenesis, the molecular mechanisms that govern TDP-43 proteostasis remain incompletely understood. Here, we investigated the role of LRSAM1, an E3 ubiquitin ligase, in regulating TDP-43 localization and degradation. Postmortem spinal cord tissues from five patients with sporadic amyotrophic lateral sclerosis and five healthy controls were examined. Immunohistochemical analyses revealed that LRSAM1 preferentially colocalized with diffusely mislocalized cytoplasmic TDP-43 but not with dense cytoplasmic aggregates, suggesting a potential role in early-stage pathological processing. To model these effects in vitro, induced pluripotent stem cell-derived motor neurons from three patients with amyotrophic lateral sclerosis and four healthy control participants were used. Knockdown of LRSAM1 in induced pluripotent stem cell-derived motor neurons from patients with amyotrophic lateral sclerosis significantly increased cytoplasmic TDP-43 accumulation and phosphorylation, as measured by immunofluorescence imaging. Moreover, STMN2 mRNA splicing, a well-established TDP-43 functional readout, was disrupted upon LRSAM1 depletion. Conversely, overexpression of LRSAM1 ameliorated stress-induced TDP-43 mislocalization and phosphorylation in induced pluripotent stem cell-derived motor neurons from patients with amyotrophic lateral sclerosis but had minimal impact in control cells, indicating disease-specific vulnerability. Mechanistically, LRSAM1 interacted directly with the aggregation-prone C-terminal fragments of TDP-43 via the RRM2 domain of TDP-43 and promoted their proteasomal degradation. This selective interaction reduced the accumulation of toxic TDP-43 species and supported cytoplasmic proteostasis, particularly under conditions of cellular stress. In summary, our study identifies LRSAM1 as a novel modulator of cytoplasmic TDP-43 dynamics in amyotrophic lateral sclerosis. By facilitating degradation of pathogenic TDP-43 fragments, LRSAM1 preserves neuronal RNA processing and mitigates molecular hallmarks of amyotrophic lateral sclerosis. These findings enhance our understanding of post-translational control of TDP-43 and highlight LRSAM1 as a promising therapeutic target for modifying disease progression in amyotrophic lateral sclerosis.

Keywords:  RNA-binding proteins; iPSC-derived motor neurons; motor neuron disease; proteasomal degradation; proteinopathy; ubiquitination

DOI:  https://doi.org/10.1093/brain/awag334
Philos Trans R Soc Lond B Biol Sci. 2026 Oct 01. pii: 20250279. [Epub ahead of print]381(1960):

Protein rheostasis: quality control in metastable proteomes.

Michele Vendruscolo.

  Protein homeostasis is often described as the capacity of cellular quality-control systems to maintain proteome function by favouring functional protein states. Yet many proteins can populate multiple states, including native conformations, liquid-like condensed assemblies, and aggregated states, reflecting the metastability of the proteome. As a framework for understanding how cells preserve proteome function under such conditions, we discuss protein rheostasis as the system that regulates thermodynamic driving forces and kinetic barriers to control the flux between alternative states over time. Framing proteome maintenance in terms of rheostatic control over the multiple states helps rationalize how ageing, stress, and mutations redistribute populations towards condensed and aggregated states by eroding kinetic buffering capacity, and it suggests therapeutic opportunities that restore control by tuning the transitions between metastable states. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.

Keywords:  liquid–liquid phase separation; protein aggregation; protein homeostasis; protein misfolding

DOI:  https://doi.org/10.1098/rstb.2025.0279