bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2026–03–08
fifteen papers selected by
Verena Kohler, Umeå University
  1. Heat shock proteins (Hsp70 and Hsp90) in neurodegeneration: pathogenic roles and therapeutic potential.
  2. TDP-43 phosphorylation: Exploring kinases, phosphatases, and therapeutic potential in neurodegeneration.
  3. Tubulin transforms Tau and α-synuclein condensates from pathological to physiological.
  4. Medicinal chemistry approaches for dual inhibition of amyloid-β and tau aggregation in Alzheimer's disease.
  5. Orchestrating pathogenesis: copper ions as the conductor of molecular dysfunction in Parkinson's disease and therapeutic avenues.
  6. Differential Responses of Amyloid-β 42 Aggregates to Resveratrol.
  7. Dual targeting of the UPS and autophagy as a novel therapy for neurodegenerative proteinopathies.
  8. Stochastic misfolding drives the emergence of distinct α-synuclein strains.
  9. CHCHD2 links mitochondrial dysfunction and α-synuclein misfolding in Parkinson's disease.
  10. Tolcapone Interferes With Key Pathological Features in Alzheimer's Disease.
  11. Nucleation dynamics in amyloid-beta dimerization revealed by single-molecule fingerprinting.
  12. Liquid-liquid phase separation modulates the structural heterogeneity of tau amyloid fibrils.
  13. Neurofilament light chain protein exposure contributes to protein aggregation, microgliosis, astrogliosis and neuroinflammation via p38/MK2/NF-κB/CREB1/Nrf2/HO-1 signalling leading to Parkinson's disease.
  14. Structural and morphological dynamics of "on-path" and "off-path" oligomers of human islet amyloid polypeptide.
  15. Proteostasis, disease and the ageing neuron: Compartmental complexity in non-renewing cells.
  1. Front Aging Neurosci. 2026 ;18 1711422
    Heat shock proteins (Hsp70 and Hsp90) in neurodegeneration: pathogenic roles and therapeutic potential.
    Noureddine Ben Khalaf.
      The maintenance of protein homeostasis is essential for neuronal survival and function; however, it progressively declines with age, predisposing the brain to neurodegenerative diseases. Molecular chaperones Hsp70 and Hsp90 are key guardians of proteostasis, pivotally regulating protein folding, refolding, and degradation under both physiological and stress conditions. This review integrates an overview of the structural features, isoforms, and mechanistic interactions of Hsp70 and Hsp90. It highlights how their dysfunction contributes to the pathogenesis of major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. We first examine the architecture and ATP-driven chaperone cycles of Hsp70 and Hsp90, their co-chaperone networks, and the feedback regulation by the Heat Shock Factor-1 pathway. We then discuss evidence linking age-related declines in chaperone expression and HSF-1 activity to proteostasis collapse and neuronal vulnerability. The review particularly examines how Hsp70 and Hsp90 differentially influence pathogenic protein aggregation (e.g., tau, α-synuclein, TDP-43, and mutant huntingtin) and how this balance is altered in the aging brain. Regarding therapeutic approaches, we summarize current strategies targeting these chaperones, including small-molecule modulators of Hsp70 and Hsp90, co-chaperone inhibitors, and recombinant chaperone therapy, which has shown to restore proteostasis and cognitive function in experimental models. These emerging interventions underscore the dual nature of Hsp70/Hsp90 systems, acting as both protectors and potential contributors to neurodegeneration, depending on their regulation and interaction context. By linking molecular chaperone biology to aging and translational therapeutics, this review establishes a framework for developing precision approaches that enhance proteostasis capacity, delay age-associated neurodegeneration, and promote healthy brain aging.
    Keywords:  alpha-synuclein; heat shock proteins; molecular chaperone; neurodegenerative diseases; proteostasis; tau
    DOI:  https://doi.org/10.3389/fnagi.2026.1711422
  2. J Alzheimers Dis. 2026 Mar 04. 13872877261424284
    TDP-43 phosphorylation: Exploring kinases, phosphatases, and therapeutic potential in neurodegeneration.
    Liti Zhang, Yichen Huang, Wei Huang, Qianqian Huang, Yizhou Lin, Jianlan Gu.
      TAR DNA-binding protein 43 (TDP-43) is a multifunctional DNA/RNA-binding protein whose abnormal phosphorylation and aggregation are central to the pathogenesis of several neurodegenerative diseases. TDP-43 proteinopathy, characterized by hyperphosphorylation and cytoplasmic accumulation, is a defining pathological feature of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and is frequently observed in Alzheimer's disease. The phosphorylation state of TDP-43 is dynamically regulated by a network of protein kinases-including CK1, GSK3β, CDC7, and PKA-and counterbalanced by phosphatases such as PP2A and PP1; however, the precise molecular mechanisms governing this equilibrium in disease remain incompletely understood. Notably, phosphorylated TDP-43 acquires prion-like properties, enabling self-templated aggregation and cell-to-cell propagation, which amplifies pathology and drives disease progression. These insights have catalyzed the development of therapeutic strategies aimed at modulating TDP-43 phosphorylation, with kinase inhibitors and phosphatase enhancers emerging as promising candidates for targeting TDP-43 proteinopathies. This review integrates current knowledge on the regulatory networks controlling TDP-43 phosphorylation, examines its role in prion-like spread, and evaluates emerging therapeutic approaches aimed at mitigating TDP-43-mediated neurodegeneration.
    Keywords:  Alzheimer's disease; TDP-43; neurodegenerative disease; phosphatase; phosphorylation; protein kinase
    DOI:  https://doi.org/10.1177/13872877261424284
  3. Nat Commun. 2026 Mar 03.
    Tubulin transforms Tau and α-synuclein condensates from pathological to physiological.
    Lathan Lucas, Phoebe S Tsoi, My Diem Quan, Kyoung-Jae Choi, Josephine C Ferreon, Allan Chris M Ferreon.
      Proteins undergo phase separation to form membraneless condensates that spatially organize biomolecular interactions. These condensates can support cellular physiology or instigate pathological protein aggregation. Tau and α-synuclein (αSyn) are neuronal proteins that form heterotypic Tau:αSyn condensates associated with physiological and pathological processes. Tau and αSyn regulate microtubules, but also misfold and co-deposit in aggregates linked to neurodegenerative disease, highlighting the ambivalent impact of Tau:αSyn condensation in health and disease. Here, we show that Tubulin modulates Tau:αSyn condensates by promoting microtubule interactions and inhibiting homotypic and heterotypic pathological oligomers. In the absence of Tubulin, Tau-driven condensation accelerates formation of pathogenic Tau:αSyn heterodimers and amyloid fibrils. Tubulin partitioning into condensates promotes microtubule polymerization and prevents Tau and αSyn oligomerization. We identify distinct Tau and αSyn structural states in pathological Tubulin-absent versus physiological Tubulin-rich condensates. In neuronal models, microtubule loss drives pathological oligomer formation and neurite loss, whereas inducible Tau condensation stabilizes microtubules.
    DOI:  https://doi.org/10.1038/s41467-026-69618-3
  4. Future Med Chem. 2026 Mar 02. 1-18
    Medicinal chemistry approaches for dual inhibition of amyloid-β and tau aggregation in Alzheimer's disease.
    Jatin Jangra, Isha Mahindru, Aman Kumar, Harikesh Kumar Gupta, Vishwakarma Krishna Ramesh, Rajnish Kumar.
      Proteinopathies play a complex interplay in the pathogenesis of multifactorial neurological disorders. In Alzheimer's disease (AD), the extracellular deposition of amyloid-β (Aβ) plaques and intracellular accumulation of hyperphosphorylated tau into neurofibrillary tangles are the two principal pathological hallmarks. In both cases, nucleation-dependent self-assembly triggers fibril formation and consequent aggregation that disrupts synaptic integrity and accelerates neuronal degeneration. The emerging interconnection between both the proteinopathies, wherein Aβ oligomers promote tau hyperphosphorylation and subsequent aggregation, highlights the need for developing multifunctional dual Aβ-tau aggregation inhibitors. Over the past decade, several dual-acting small molecules have been reported, including synthetic scaffolds (sulfonamides, thiophenes, acridones, isoquinolinium analogues), semi-synthetic derivatives (curcumin, tacrine, ferulic acid), and naturally derived compounds (neferine, pyrogallol, chrysin). While these molecules demonstrate promising in vitro inhibition of both Aβ and tau aggregation through the disruption of β-sheet formation and, in some cases, disaggregation of preformed fibrils; however, their translational potential is often constrained by suboptimal brain penetration, moderate potency, or limited correlation between aggregation inhibition and neuroprotection. This review provides comprehensive molecular mechanisms of Aβ and tau aggregation and a detailed structure-activity relationships (SAR) of reported dual inhibitors to guide the rational design of future novel multitarget therapeutics with improved drug-likeness and disease-modifying potential for AD.
    Keywords:  Alzheimer’s disease; Dementia; SAR; Thioflavin T; amyloid β; proteinopathy; small molecule inhibitors; tau aggregation
    DOI:  https://doi.org/10.1080/17568919.2026.2636501
  5. Rev Neurosci. 2026 Mar 04.
    Orchestrating pathogenesis: copper ions as the conductor of molecular dysfunction in Parkinson's disease and therapeutic avenues.
    Zhe Zhang, Yanning Cai, Lingling Lu.
      Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the abnormal aggregation of α-synuclein (α-Syn) into Lewy bodies. While these pathological features arise from genetic susceptibility, environmental exposures, and age-related cellular deteriorations, the precise interactions among these factors remain incompletely understood. Mounting evidence implicates that copper ions are playing a critical role in PD pathogenesis, particularly in regulating dopaminergic neuron survival and the aggregation dynamics of α-Syn.
    Keywords:  Parkinson’s disease; copper metabolism; cuproptosis; oxidative stress; targeted therapy; α-synuclein
    DOI:  https://doi.org/10.1515/revneuro-2025-0134
  6. Adv Biol (Weinh). 2026 Mar;10(3): e00586
    Differential Responses of Amyloid-β 42 Aggregates to Resveratrol.
    Nghia D Nguyen, Peter G Vekilov.
      Amyloid-β (Aβ) aggregation is targeted with small molecules as a pathway toward developing potential Alzheimer's disease (AD) therapies. Resveratrol, a natural polyphenol, has been proposed as an inhibitor of Aβ aggregation, but its mechanistic effects across distinct Aβ42 aggregates remain unresolved. To better evaluate resveratrol's potential to treat AD, here we focus on molecular-level insights into the mechanisms that underlie its interaction with several distinct classes of Aβ42 aggregates. In contrast to published approaches that are based on monitoring the evolution of the total fibrillar mass, we employ time-resolved in situ atomic force microscopy to explore the effects of resveratrol on Aβ42 amyloid and non-amyloid assemblies. While data suggest a weak interaction between resveratrol and low-molecular-weight Aβ42 species, we also observe a concentration-dependent reduction in fibrillization. In the presence of resveratrol, we observe a decrease in fibril thickness and end-dependent slowing of elongation; furthermore, the fibrils exhibit reduced mechanical integrity and fragment under minimal scanning stress. Importantly, resveratrol does not affect the formation or morphology of oligomers and amorphous aggregates. These findings suggest that resveratrol selectively targets the fibril pathway while leaving oligomeric assemblies unaltered. The results provide mechanistic insights into the differential effects of small molecules on Aβ42 assemblies and establish a framework for evaluating inhibitors of aggregation with single-aggregate resolution.
    Keywords:  amyloid‐beta 42; mechanisms of inhibition; resveratrol; structural diversity
    DOI:  https://doi.org/10.1002/adbi.202500586
  7. Front Cell Neurosci. 2026 ;20 1738415
    Dual targeting of the UPS and autophagy as a novel therapy for neurodegenerative proteinopathies.
    Georgie Lines, Martin Helley, Sébastien Gillotin, Janet Brownlees, James Duce, Phillip Smethurst.
      Neurodegenerative proteinopathies are characterized by impaired protein clearance and the accumulation of misfolded or aggregated proteins, ultimately leading to neuronal death. The two principal pathways responsible for protein degradation in cells are the ubiquitin proteasome system (UPS) and autophagy. Emerging evidence indicates that these pathways share regulatory components and engage in extensive crosstalk. In this review, we summarize the mechanisms of the UPS and autophagy, highlight their points of interaction, and discuss therapeutic opportunities to modulate both systems in parallel to enhance protein clearance in neurodegenerative disease.
    Keywords:  UPS—ubiquitin proteasome system; autophagy; neurodegenearation; neurodegenerative diseases; proteasome; therapeutics
    DOI:  https://doi.org/10.3389/fncel.2026.1738415
  8. Neuron. 2026 Feb 27. pii: S0896-6273(26)00040-1. [Epub ahead of print]
    Stochastic misfolding drives the emergence of distinct α-synuclein strains.
    Raphaella W L So, Benedikt Frieg, José D Camino, Christopher Situ, Mark N Metri, Nicholas R G Silver, Le Yao Li, Alison Mao, Erica Stuart, Gunnar F Schröder, Joel C Watts.
      α-Synuclein conformational strains provide a potential explanation for the clinical and pathological differences among synucleinopathies such as Parkinson's disease and multiple system atrophy. However, how distinct α-synuclein strains arise remains unknown. Here, we observed conformational heterogeneity between individual preparations of α-synuclein pre-formed fibrils (PFFs) generated by polymerizing wild-type or A53T-mutant human α-synuclein under identical conditions. Moreover, we found that α-synuclein aggregates formed spontaneously in the brains of a transgenic synucleinopathy mouse model are conformationally diverse. Propagation of stochastically formed PFF- and brain-derived α-synuclein strains in mice initiated several distinct synucleinopathies. The conformational diversity of α-synuclein aggregates across PFF preparations and between individual mice demonstrates that α-synuclein can spontaneously form multiple self-propagating strains within an identical environment. This suggests that stochastic misfolding into distinct aggregate structures drives the emergence of α-synuclein strains and reveals that the intrinsic variability of common synucleinopathy research tools must be considered when designing and interpreting experiments.
    Keywords:  Parkinson's disease; cryo-electron microscopy; dementia with Lewy bodies; multiple system atrophy; pre-formed fibrils; prion-like propagation; protein aggregation; strain; transgenic mice; α-synuclein
    DOI:  https://doi.org/10.1016/j.neuron.2026.01.014
  9. Trends Neurosci. 2026 Feb 27. pii: S0166-2236(26)00026-3. [Epub ahead of print]
    CHCHD2 links mitochondrial dysfunction and α-synuclein misfolding in Parkinson's disease.
    Derek Narendra, Brent J Ryan.
      Parkinson's disease comprises multiple biological subtypes and a heterogeneous clinical course. A recent study by Liao et al. identifies CHCHD2 mutations as a mitochondrial entry point that links metabolic dysfunction to α-synuclein pathology. These findings highlight how rare sporadiclike monogenic forms of Parkinson's disease may inform mechanistic and therapeutic stratification.
    Keywords:  disease stratification; dopaminergic neurons; mitochondrial metabolism; neurodegeneration; oxidative stress; protein aggregation
    DOI:  https://doi.org/10.1016/j.tins.2026.02.002
  10. Bioinorg Chem Appl. 2026 ;2026 1036276
    Tolcapone Interferes With Key Pathological Features in Alzheimer's Disease.
    Alessia Distefano, Damiano Calcagno, Giuseppe Grasso, Olivier Monasson, Elisa Peroni, Valentina Oliveri.
      Tolcapone, a clinically approved drug for the treatment of Parkinson's disease as an adjunct therapy, has recently emerged as a potential modulator of amyloid-β aggregation and toxicity, which are hallmark features of Alzheimer's disease and are also involved in ocular neurodegenerative disorders, including glaucoma and age-related macular degeneration. Despite these noteworthy findings, the molecular basis of the interaction between amyloid-β and tolcapone remains poorly understood, and the mechanisms by which tolcapone affects metal-amyloid-β species have yet to be explored. In this work, we investigate the binding interactions of tolcapone with both copper-free amyloid-β and copper-associated amyloid-β complexes, using a combination of techniques including UV-vis spectroscopy, circular dichroism, mass spectrometry, and surface plasmon resonance. The results reveal that tolcapone binds directly to amyloid-β monomers. Furthermore, in vitro assays confirm the capacity of tolcapone to act as a radical scavenger and to compete with amyloid-β for the binding of copper ions. Altogether, our findings suggest that tolcapone exerts a multifaceted protective effect, potentially inhibiting toxic metal-free and metal aggregation pathways by preventing metal coordination to amyloid-β or disrupting preformed amyloid-β-metal complexes, thus offering new perspectives to explore and develop its analogs for the treatment of neurodegenerative disorders.
    Keywords:  aggregation; amyloid-beta; antioxidant; binding constant; neurodegeneration; tolcapone
    DOI:  https://doi.org/10.1155/bca/1036276
  11. Cell Rep Phys Sci. 2025 Nov 19. pii: 102930. [Epub ahead of print]6(11):
    Nucleation dynamics in amyloid-beta dimerization revealed by single-molecule fingerprinting.
    A K M Kafi, Mathias Bogetoft Danielsen, Shixi Song, Deepak Karna, Sajan Shakya, Jiahao Ji, Yitong Hao, Pelayo Alvarez Penanes, Frank Kjeldsen, Hanbin Mao, Chenguang Lou.
      The aggregation of amyloid-beta (Aβ) peptides ( Aβ1-40 or Aβ1-42 ) is closely related to the pathology of Alzheimer's disease (AD). Soluble oligomers that appear during Aβ aggregation are primary neurotoxic species; however, their misfolding kinetics have yet to be determined. Here, we report a bottom-up construction of parallel and antiparallel Aβ1-40 dimers, the first oligomers formed during Aβ aggregation. We apply single-molecule mechanical unfolding in optical tweezers to investigate the dynamic structural evolution of these dimers at the single-amino-acid resolution. We observe three intermediates during the association and dissociation of individual Aβ1-40 dimers, with the diphenylalanine Aβ19-20 dimer having the highest formation probability. Our single-molecule fingerprinting method reveals that a known Aβ aggregation inhibitor, rosmarinic acid, can reduce Aβ1-40 dimerization by binding to the Aβ19-20 site. We anticipate that the molecular tool innovated in our study is extensible to investigating other amyloid aggregations responsible for a myriad of neurodegenerative diseases.
    DOI:  https://doi.org/10.1016/j.xcrp.2025.102930
  12. J Mol Biol. 2026 Mar 03. pii: S0022-2836(26)00110-5. [Epub ahead of print] 169737
    Liquid-liquid phase separation modulates the structural heterogeneity of tau amyloid fibrils.
    Ishtiyaq A Ganaie, Jayant B Udgaonkar.
      The protein tau can undergo two types of phase transitions, amyloid fibrillar aggregation leading to neurodegenerative disease, as well as liquid-liquid phase separation (LLPS) leading to the formation of protein condensates. The link between these two processes has yet to be understood fully. In this study, the tau construct, tau (243-386), was found to undergo LLPS only below a NaCl concentration of 135 mM. Hence, fibril formation was studied in 100 and 150 mM NaCl, on either side of the phase boundary established by the salt. Protein molecules inside the condensates lost their dynamicity, as measured by the extent of fluorescence recovery after photobleaching, with a characteristic time similar to that for the formation of amyloid aggregates. Thioflavin T fluorescence intensity increased homogeneously throughout the condensate interior, indicating that amyloid aggregate formation was not restricted to the interface, and with kinetics identical to that observed in a bulk measurement of amyloid fibril formation. Fibrils were seen to be emerging from aged condensates. Hydrogen-deuterium exchange studies coupled to mass spectrometry showed that tau undergoes heterogeneous fibril formation, with structurally different populations of fibrils forming under the same conditions. The structures and local stabilities of the protein molecules assembled inside the fibrils differed when formed under the LLPS and non-LLPS conditions. Consequently, the structural heterogeneity of fibrils formed under LLPS conditions was distinct from that of fibrils formed under non-LLPS conditions. The results indicate that LLPS might facilitate the selective formation of a particular structural polymorph in a heterogeneous fibril population.
    Keywords:  hydrogen-deuterium exchange mass spectrometry; liquid-liquid phase separation; nucleation-dependent polymerization; polymorphism; tauopathies
    DOI:  https://doi.org/10.1016/j.jmb.2026.169737
  13. Int J Biol Macromol. 2026 Mar 02. pii: S0141-8130(26)01076-7. [Epub ahead of print] 151150
    Neurofilament light chain protein exposure contributes to protein aggregation, microgliosis, astrogliosis and neuroinflammation via p38/MK2/NF-κB/CREB1/Nrf2/HO-1 signalling leading to Parkinson's disease.
    Anjuman Nanda, Shivam Kumar Pandey, Rakesh Kumar Singh.
      The neurofilament light chain (NfL) is a well-established biomarker specific to neuronal structural integrity across various neurodegenerative conditions, including Parkinson's disease. (PD). This research investigated how the NfL protein may actively contribute to PD progression by comparing its effects with those of the 6-hydroxydopamine (6-OHDA)-induced mouse model. Atomic force microscopy (AFM) was used to characterise NfL aggregation and fibril morphology before injection. We monitored movement, coordination, and cognitive abilities in animals on days 0, 14, and 28 following injections. We evaluated various molecular biochemical changes, including the expression of the proinflammatory and apoptotic proteins, expression of dopamine transporter (DAT), neuronal nuclear marker (NeuN) and gliosis markers (GFAP and IBA-1) and colocalization of tyrosine hydroxylase (TH) and α-synuclein accumulation to simultaneously assess hallmarks of dopaminergic pathology in the striatum and substantia nigra pars compacta (SNpc) regions of the brain on day 28 post-surgery. NfL exposure led to a significant change in movement, induction of anxiety-like symptoms, and reduced cognitive behaviours. We found a marked reduction in the levels of TH, accompanied by an increased α-synuclein accumulation. We also observed a reduction in dopamine transporter (DAT) and neuronal nuclear antigen (NeuN) expression in both these regions. Furthermore, NfL exposure impaired oxidative balance, activated proinflammatory biomarkers and gliosis in a dose-dependent manner. This study has provided a direct evidence on the pathological role of NfL exposure and its aggregation in vivo, offering new mechanistic insights into NfL-induced PD progression in animals.
    Keywords:  Neurofilament light chain (NfL); Parkinson's disease; α-Synuclein aggregation
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.151150
  14. Protein Sci. 2026 Apr;35(4): e70523
    Structural and morphological dynamics of "on-path" and "off-path" oligomers of human islet amyloid polypeptide.
    Daniel Warren, Jadon Sitton, Dmitry Kurouski.
      The deposition of cytotoxic human islet amyloid polypeptide (IAPP) aggregates is a hallmark feature of Type 2 Diabetes. However, the structural evolution and cytotoxicity of IAPP aggregate species remain poorly understood. This study combines kinetics, biophysical and cell assays to resolve the morphological dynamics of IAPP aggregation. Using atomic force microscopy (AFM) and atomic force microscopy Infrared (AFM-IR) spectroscopy, we observed two distinctly different types of oligomers, donut-like (DO) and round oligomers (RO), formed at the early stages of protein aggregation. DO were dominated by parallel β-sheet secondary structure. Their evanescence is linked to the formation of IAPP fibrils, which also had parallel β-sheet secondary structure. In contrast, RO had primarily disordered secondary structure and persisted throughout the course of fibril formation. This structural and kinetic analyses showed that RO were "off-path", while DO were "on-path" protein aggregates. Cell toxicity assays indicated that structural evolution of IAPP amyloids as well as persistent "off-path" oligomeric species both contribute to high cytotoxicity in pancreatic β cells. These results revealed a complex mechanism of IAPP aggregation which is highly important in the context of the prevention of pathological protein aggregation.
    Keywords:  AFM‐IR; IAPP; fibrils; oligomers; type 2 diabetes
    DOI:  https://doi.org/10.1002/pro.70523
  15. Ageing Res Rev. 2026 Feb 27. pii: S1568-1637(26)00065-6. [Epub ahead of print]118 103073
    Proteostasis, disease and the ageing neuron: Compartmental complexity in non-renewing cells.
    Rosemary A Coleman, Michaela E Johnson, Anna Konopka, Yee Lian Chew.
      Proteostasis, the maintenance of protein homeostasis, is a critical cellular process for neuronal health that declines with age, contributing to neurodegenerative disease. This review examines the molecular architecture of the proteostasis network, how this is disrupted in ageing neurons, and its impact on neuronal function. We discuss unique challenges posed by the complexity arising from distinct neuronal compartments with distinct functions, as well as neurons' high energy demands, and post-mitotic status. We next detail how proteostasis mechanisms differ across neuronal compartments and neural subtypes, and how these differences influence susceptibility to stress and disease. Finally, we explore how these differences shape selective vulnerability in neurodegenerative diseases. By integrating recent transcriptomic and proteomic insights, this review highlights the need for compartment- and cell-type-specific approaches to mitigate proteostasis collapse in the ageing brain.
    Keywords:  Ageing; Axon; Dendrite; Neurodegeneration; Proteostasis
    DOI:  https://doi.org/10.1016/j.arr.2026.103073
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