bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2026–07–26
seven papers selected by
Verena Kohler, Umeå University
  1. Deciphering the mechanism of protein aggregation and effects of inhibitors using single-molecule mass photometry.
  2. From synaptic development to degeneration: a narrative review of small molecule strategies targeting alpha-synuclein in Parkinson's disease.
  3. Metal-organic macrocycles as molecular modulators of amyloid-β aggregation and cytotoxicity.
  4. Complement dysregulation during the early phases of synucleinopathy.
  5. Conformational Bifurcation of Tau R3-R4 Oligomers Underlies Fibril Polymorphism.
  6. USP28 Deficiency is Linked to Impaired Ubiquitin-dependent Proteostasis in Huntington's Disease.
  7. Exploring shared genetic pathways and gene interplay in major neurodegenerative diseases: a comprehensive review.
  1. Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2536600123
    Deciphering the mechanism of protein aggregation and effects of inhibitors using single-molecule mass photometry.
    Aaron Lyons, Simanta Sarani Paul, Jack E MacArthur, Grace N Hoffman, Allan Yarahmady, Sue-Ann Mok, Michael T Woodside.
      Aggregation of misfolded proteins is a prominent feature of many diseases and hence an attractive drug target. However, the small oligomers that are critical early species in the aggregation cascade are difficult to monitor directly owing to their heterogeneity and transience, complicating efforts to define aggregation mechanisms and target oligomers therapeutically. Here, we observe changes in oligomer populations directly using single-molecule mass photometry (MP). Studying the pathogenic P301L mutant of tau protein linked to frontotemporal dementia, we globally fit the growth/decay kinetics for every oligomer population observed by MP to microscopic models of aggregation. A simple extension to the best-fit model also accounts for amyloid fibril kinetics, as monitored by Thioflavin T fluorescence, providing a quantitative model of aggregation kinetics across all stages of the cascade based on direct observation. Crucially, we find that models fitting amyloid kinetics alone fail to capture oligomer behavior, implying that-contrary to standard practice-amyloid kinetics cannot be relied on to deduce aggregation mechanisms. Furthermore, there is no single rate-limiting nucleation step preceding rapid growth, as generally assumed, suggesting that standard models of aggregation are overly simplistic. Repeating the analysis in the presence of aggregation inhibitors allows identification of the discrete steps in the cascade affected by the inhibitors. This work presents a powerful approach for defining protein aggregation mechanisms and the mechanism of action of inhibitors, with applications to understanding many diseases and developing novel therapeutics.
    Keywords:  aggregation inhibitors; kinetic mechanisms; mass photometry; protein aggregation; tau protein
    DOI:  https://doi.org/10.1073/pnas.2536600123
  2. Metab Brain Dis. 2026 Jul 23. pii: 174. [Epub ahead of print]41(1):
    From synaptic development to degeneration: a narrative review of small molecule strategies targeting alpha-synuclein in Parkinson's disease.
    Leanne Khoo, Khuen Yen Ng, Cien Leong Chye, Yi Ko, Jia Yee Lee, Yian Koh, Min Tze Tsen, Soi Moi Chye.
      Aggregation of α-synuclein (α-Syn) is a defining pathological feature of Parkinson's disease (PD), contributing to progressive neuronal dysfunction and death. Unlike prior reviews focused predominantly on aggregation as an isolated endpoint, this review proposes a neurodevelopmental-neurodegenerative continuum as an interpretive framework, suggesting that α-Syn's physiological roles in synaptic development and circuit maturation may be linked to its later pathological behaviour. Within this context, we discuss recent advances in small-molecule strategies targeting key stages of α-Syn pathology, including synthesis, misfolding, aggregation, post-translational modification, and clearance. These include translation and misfolding inhibitors, aggregation modulators such as minzasolmin (UCB0599), epigallocatechin gallate and anle138b, as well as compounds that enhance α-Syn degradation through autophagy-lysosomal and ubiquitin-proteasome pathways. Additional strategies targeting proteostasis and mitochondrial dysfunction are also considered. Beyond its pathogenic role, α-Syn contributes to synaptic vesicle trafficking, neurotransmitter release, and neuronal maturation, and disruption of these functions may increase vulnerability to later neurodegeneration. In conclusion, small-molecule-based therapies represent a promising multi-targeted strategy for PD; however, key translational challenges and unresolved questions remain, including optimisation of pharmacokinetics, target specificity, and blood-brain barrier (BBB) penetration and validation in clinical settings.
    Keywords:  Alpha-synuclein; Parkinson’s disease; Post-translational modifications; Small molecules
    DOI:  https://doi.org/10.1007/s11011-026-01911-y
  3. Chem Sci. 2026 Jul 15.
    Metal-organic macrocycles as molecular modulators of amyloid-β aggregation and cytotoxicity.
    Chanju Na, Gajendra Gupta, Mingeun Kim, Yena Choe, Junseong Lee, Chang Yeon Lee, Mi Hee Lim.
      Metal-organic macrocycles provide a versatile platform for integrating multiple chemical functions within a single, well-defined architecture, yet their potential for regulating pathological protein aggregation remains largely unexplored. Here we report rationally designed metal-organic macrocycles that combine piano-stool ruthenium or iridium complexes with a photoactivatable bis(difluoroboron)-1,2-bis((1H-pyrrol-2-yl)methylene)hydrazine (BOPHY)-based ligand to enable dual-mode modulation of amyloid-β (Aβ) aggregation associated with Alzheimer's disease. These macrocycles directly engage Aβ species through surface interactions and, upon light activation, induce oxidative modifications via singlet oxygen, collectively altering aggregation behavior and aggregate morphologies. As a result, they suppress the formation of toxic Aβ assemblies and attenuate Aβ-induced cytotoxicity. Overall, this work establishes metal-organic macrocycles as effective modulators of amyloidogenesis and provides a potential strategy for controlling complex protein aggregation processes in neurodegenerative diseases.
    DOI:  https://doi.org/10.1039/d6sc04289a
  4. Acta Neuropathol. 2026 Jul 20. pii: 7. [Epub ahead of print]152(1):
    Complement dysregulation during the early phases of synucleinopathy.
    Hina Khan, Mary Gifford, Arash Kordbacheh, Asher Bury, Spencer Panoushek, Allyson Cole-Strauss, Christopher J Kemp, Kelvin C Luk, Kathy Steece-Collier, Nathan C Kuhn, Nicholas M Kanaan, Caryl E Sortwell, Joseph R Patterson, Matthew J Benskey.
      Parkinson's disease (PD) is characterized by progressive degeneration of nigrostriatal dopamine neurons and synucleinopathy, which is the accumulation of aggregated α-synuclein (α-syn). Increasing evidence implicates α-syn-associated neuroinflammation as a contributor to PD pathogenesis, yet immune mechanisms linking synucleinopathy to neurodegeneration remain incompletely defined. Activation of the complement cascade occurs in PD and other synucleinopathies, but most studies report complement activation after overt neurodegeneration, making it difficult to conclude if complement is directly activated by pathological α-syn or secondarily following neurodegeneration. We used the rat α-syn preformed fibril (PFF) model, in vitro complement assays and postmortem human PD tissue to investigate whether pathological α-syn directly activates complement prior to overt neurodegeneration. The α-syn PFF model exhibits a protracted pathological time course and distinct temporal separation between peak α-syn aggregation and nigrostriatal degeneration. Thus, we quantified complement expression, activation, and regulation during the aggregation phase. Synucleinopathy caused complement activation prior to nigrostriatal degeneration, including upregulation of components of both the classical (C1qa, C1r, C4b) and alternative (Cfd, Cfb) pathways, the anaphylatoxin (C3aR, C5aR) and phagocytic (CR3) complement receptors, and activation of complement C3. During early synucleinopathy microglia upregulated C3, which significantly correlated with synucleinopathy burden across several brain regions, including the substantia nigra pars compacta (SNc) and cortex. Concurrently, complement regulators, including Cd55, Cd59, neuronal pentraxin-1 (Nptx1), and the neuronal pentraxin receptor were downregulated in the synucleinopathy-affected SNc. Importantly, increased levels of C1q and iC3b along with downregulation of CD55 and NPTX1 protein were also observed in human postmortem PD SNc tissue, supporting the translational relevance of our findings. Mechanistically, we demonstrate that aggregated, but not monomeric, α-syn directly binds C1q and activates the complement cascade in a C1q-dependent manner. These data provide the first in vivo evidence that synucleinopathy triggers complement activation and dysregulation prior to neurodegeneration.
    Keywords:  Alpha-synuclein; Complement system; Neurodegeneration; Neuroinflammation; Parkinson’s disease; Synucleinopathy
    DOI:  https://doi.org/10.1007/s00401-026-03057-8
  5. Biophys J. 2026 Jul 18. pii: S0006-3495(26)00515-1. [Epub ahead of print]
    Conformational Bifurcation of Tau R3-R4 Oligomers Underlies Fibril Polymorphism.
    Tong Zhang, Lingling Dai, Yanping Ma, Shicai Xu, Xiangdong Liu, Mingwen Zhao, Weifeng Li, Jiayong Wang, Yang Liu.
      Tau aggregation into amyloid fibrils is a central pathological feature of multiple neurodegenerative diseases, yet identical tau sequences can adopt structurally distinct fibril conformations associated with different disorders. How such disease-specific folds emerge from the same sequence remains poorly understood. Here, we use metadynamics and all-atom molecular dynamics simulations to elucidate the folding mechanisms of tau trimers comprising the R3-R4 region, the minimal aggregation nucleus of tau fibrils. By constructing the folding free-energy landscape within a pre-organized fibril-like scaffold, we identify a shared, partially folded intermediate from which two energetically comparable minimum free-energy pathways (MEPs) diverge, leading to either a compact AD-like or a more open CTE-like C-shaped conformation. Structural analysis reveals that the β4-β6 triangular region acts as the central determinant of this bifurcation. Hydrophobic-core rearrangements within this region provide the primary energetic driving force for compaction, whereas the conformational flexibility of the 332PGGG335 hinge modulates whether this tendency can be structurally realized. Additional simulations show that stable formation of the triangular region requires cooperative multichain interactions; reducing oligomer size destabilizes this scaffold and abolishes ordered folding. Together, our results establish a mechanistic framework in which identical tau sequences access alternative folding routes through a common intermediate, explaining the emergence of disease-specific fibril polymorphism at the oligomeric level and highlighting early folding intermediates as potential targets for therapeutic intervention.
    DOI:  https://doi.org/10.1016/j.bpj.2026.07.020
  6. Mol Neurobiol. 2026 Jul 20. pii: 780. [Epub ahead of print]63(1):
    USP28 Deficiency is Linked to Impaired Ubiquitin-dependent Proteostasis in Huntington's Disease.
    Kyoungjoo Cho, Eun Jin Park.
      Huntington's disease (HD) is characterized by mutant huntingtin (mHTT) aggregation and impaired proteostasis; however, upstream regulators of ubiquitin system imbalance remain incompletely understood. This study identified the deubiquitinase USP28 as a potential modulator of ubiquitin-dependent proteostasis in HD. Bulk RNA sequencing of R6/2 mouse brain tissues showed reduced USP28 expression compared with wild-type controls. Consistently, USP28 expression decreased in STHdh striatal cells expressing expanded polyQ huntingtin (Q111). HD cells (STHdh-Q111) exhibited increased accumulation of ubiquitinated proteins and altered ubiquitin turnover, consistent with impaired proteostasis. USP28 overexpression attenuated ubiquitinated protein accumulation and reduced mHTT aggregation, whereas a catalytically inactive USP28 mutant showed limited rescue effects. In addition, USP28 depletion was associated with reduced UBR5 levels, while USP28 restoration partially recovered UBR5 expression in a catalytic activity-dependent manner. Modulation of HECT E3 ligase activity further altered ubiquitination dynamics and mHTT aggregation, suggesting that HECT E3 ligase-related pathways may contribute to proteostasis regulation in HD cells. Collectively, these findings identify USP28 as a proteostasis-associated deubiquitinase reduced in HD models and suggest that USP28 deficiency contributes to ubiquitin burden and mHTT aggregation. Changes in UBR5 expression further point to a potential involvement of HECT E3 ligase-linked ubiquitin regulation, although the direct mechanistic relationship between USP28 and UBR5 remains.
    Keywords:  Huntington’s disease; Protein aggregation; Proteostasis; UBR5; USP28; Ubiquitin–proteasome system
    DOI:  https://doi.org/10.1007/s12035-026-06073-7
  7. Gene. 2026 Jul 20. pii: S0378-1119(26)00328-8. [Epub ahead of print]1010 150318
    Exploring shared genetic pathways and gene interplay in major neurodegenerative diseases: a comprehensive review.
    Priyanka Priyadarshini Pattnaik, Shakti Ketan Prusty, Sanghamitra Pati, Kiran Anjum Jew, Anirban Kumar Bora, Jyotirmaya Sahoo, Pratap Kumar Sahu.
      Neurodegenerative diseases are progressive disorders that involve the loss and dysfunction of neurons. Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, Frontotemporal dementia are examples of diseases. While different clinically, these disorders have a common genetic, molecular and cellular basis. This review examines the common genetic pathways, along with the interactions between genes of major neurodegenerative diseases, with a focus on the key genes, such as APOE, SNCA, MAPT, TARDBP, LRRK2 and HTT. The common pathogenic mechanisms considered to play a major role in disease progression include protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation, diminished autophagy, and impaired lysosomal function, as well as synaptic degeneration. The review also emphasizes the role of systems biology strategies, such as genome-wide association studies, transcriptomics, proteomics, metabolomics, interactome analysis, and multi-omics integration, to unveiling complex molecular networks in neurodegeneration. Furthermore, the emerging biomarker strategies and therapeutic strategies targeting convergence signaling pathways including NF-κB, PI3K-Akt-mTOR, MAPK and Wnt/β-catenin are summarized. The common genetic basis and the cross-connecting molecular mechanisms of the various neurodegenerative diseases could help in the discovery of new biomarkers and pan-therapeutic targets. Further advances in molecular genetics, computational biology and precision medicine are needed to enhance early detection and the creation of effective disease-modifying treatments.
    Keywords:  Biomarkers; Gene interplay; Multi-omics; Neurodegeneration; Neuroinflammation; Precision medicine; Protein aggregation
    DOI:  https://doi.org/10.1016/j.gene.2026.150318
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