bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2026–08–16
nine papers selected by
Verena Kohler, Umeå University
  1. α-Synuclein burden amplification in Parkinson's disease: a unified genetic, molecular, and cellular framework.
  2. Structural basis of α-synuclein and DJ-1 complex.
  3. Research progress on the α-synuclein-lysosome axis in Parkinson's disease: molecular mechanisms of protein aggregation, autophagy dysfunction, and therapeutic targeting.
  4. Dual roles of condensates in protein misfolding and aggregation.
  5. Liquid-liquid phase-separated tau colocalizes with and stabilizes Aβ oligomers.
  6. Dendritic translation and neuroproteasome-mediated degradation of endogenous tau revealed by STARFISH.
  7. The Interactions of Tau, RNA, and Stress Granules in Neurodegenerative Disease: A Comprehensive Review.
  8. Protein Self-Interaction in Cellular Function and Network Evolution: Molecular Mechanisms, AI-Driven Insights, and Therapeutic Potentials.
  9. Peroxynitrite-induced structural remodeling and aggregation of hemoglobin under nitroxidative stress.
  1. Front Neurol. 2026 ;17 1924943
    α-Synuclein burden amplification in Parkinson's disease: a unified genetic, molecular, and cellular framework.
    Sachiko Noda, Nobutaka Hattori.
       Introduction: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized pathologically by the accumulation and propagation of α-synuclein (α-syn). Although α-syn aggregation is considered central to PD pathogenesis, increasing evidence suggests that α-syn abundance may be as important as its conformational state. Genetic studies have demonstrated an SNCA dosage effect, with gene duplication and triplication associated with progressively more severe familial PD phenotypes. Complementary evidence indicates that dysfunction of protein clearance pathways, particularly the autophagy-lysosome system, promotes intracellular α-syn accumulation and increases its neurotoxic potential. In this review, we propose α-syn multiplication as an integrative framework for interpreting PD pathogenesis. This concept extends beyond SNCA copy-number variation to encompass processes that increase the effective α-syn burden within neurons or across neural networks, including increased gene expression, impaired degradation, disrupted proteostasis, and pathological propagation.
    Methods: We summarize α-syn structural dynamics and the concentration-dependent distribution of monomeric, oligomeric, and fibrillar species. We then review evidence from SNCA gene-dosage studies and examine the role of the autophagy-lysosome pathway in regulating α-syn homeostasis, with particular emphasis on recent experimental findings demonstrating that autophagy deficiency exacerbates α-syn accumulation and neurodegeneration in human α-syn bacterial artificial chromosome transgenic mice.
    Results: Collectively, the available genetic, biochemical, and experimental evidence supports a model in which the balance between α-syn production and clearance influences disease progression alongside protein misfolding. The interaction between increased protein burden and impaired clearance capacity provides a unifying mechanism linking familial and sporadic forms of PD.
    Discussion: We propose that α-syn multiplication offers an integrative framework for understanding PD pathogenesis, provides a quantitative perspective on disease heterogeneity, and highlights therapeutic opportunities aimed at reducing α-syn burden and restoring proteostatic balance.
    Keywords:  Parkinson’s disease; SNCA; autophagy–α-synuclein homeostasis; neurodegeneration; protein aggregation; α-synuclein
    DOI:  https://doi.org/10.3389/fneur.2026.1924943
  2. Int J Biol Macromol. 2026 Aug 12. pii: S0141-8130(26)03967-X. [Epub ahead of print] 154021
    Structural basis of α-synuclein and DJ-1 complex.
    Hyeon Jin Kim, Da Hye Kim, Chang Woo Han, Mi Suk Jeong, Se Bok Jang.
      The structure of α-synuclein is predominantly α-helical when bound to cellular membranes. However, under pathological or destabilizing conditions, this α-helical structure transitions into β-sheet-rich conformations, promoting protein aggregation and formation of Lewy bodies (LBs) in neurodegenerative disorders such as Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and Alzheimer's disease (AD). DJ-1 is a multifunctional brain protein acting as a chaperone or protease under oxidative stress and associating with abnormal protein aggregates. Although previous studies suggested DJ-1 inhibits α-synuclein aggregation, the structural basis remained elusive. Here, we elucidate the direct interaction between α-synuclein and DJ-1 using size-exclusion chromatography (SEC), fluorescence spectroscopy, and multi-angle light scattering (MALS), and determined their crystal structure by X-ray diffraction. The interaction interface was mapped to residues Q24, E28, A29, and N65 of α-synuclein and K148, N173, and Q180 of DJ-1, with Q180 forming strong hydrogen bonds (2.60-2.97 Å) with α-synuclein. Transmission electron microscopy (TEM) demonstrated DJ-1 suppresses α-synuclein fibril formation. Based on the structure, we designed a DJ-1-derived peptide (173-180) that significantly inhibited α-synuclein aggregation in TEM and ELISA assays, suggesting its potential as a therapeutic candidate for α-synucleinopathies.
    Keywords:  Complex; DJ-1; X-ray crystallography; α-Synuclein
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.154021
  3. Front Neurosci. 2026 ;20 1885103
    Research progress on the α-synuclein-lysosome axis in Parkinson's disease: molecular mechanisms of protein aggregation, autophagy dysfunction, and therapeutic targeting.
    Jiaojiao Fu, Chuanxi Zhu, Zhenzhen Fan.
      Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterized pathologically by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies, which predominantly consist of misfolded α-synuclein (α-Syn) aggregates. Recent advances have highlighted the critical role of the interplay between α-Syn and lysosomal function, termed the α-Syn-lysosome axis, as a central mechanism underlying PD pathogenesis. This review systematically summarizes the molecular mechanisms driving α-Syn aggregation and the lysosomal dysfunction contributing to impaired autophagy-lysosome pathway (ALP) activity. We further discuss emerging therapeutic strategies targeting this axis to restore lysosomal function and mitigate α-Syn toxicity. By integrating the latest findings from molecular biology, cell biology, and preclinical studies, this article aims to elucidate the complex regulatory network of the α-Syn-lysosome axis and provide a theoretical foundation for the development of novel therapeutic interventions for PD.
    Keywords:  Parkinson’ s disease; autophagy; lysosome; protein aggregation; α-synuclein
    DOI:  https://doi.org/10.3389/fnins.2026.1885103
  4. Curr Opin Struct Biol. 2026 Aug 14. pii: S0959-440X(26)00137-5. [Epub ahead of print]101 103355
    Dual roles of condensates in protein misfolding and aggregation.
    Emre Pekbilir, Dorothee Dormann.
      Protein aggregation is a hallmark in several neurodegenerative diseases, in which proteins assemble into structurally diverse misfolded states, ranging from amorphous aggregates to amyloid fibrils. Several aggregation-prone proteins can undergo phase separation to form biomolecular condensates, creating distinct chemical environments compared to the surrounding dilute phase. These environments dictate protein conformations, interaction networks, and free energy landscapes, thereby modulating aggregation pathways. Notably, condensates exert dual and context-dependent effects: they can promote aggregation by stabilizing misfolded intermediates and facilitating assembly, or they can suppress aggregation by buffering interactions and retaining proteins. Here, we summarize the current literature and describe biomolecular condensates as key regulators of protein misfolding and aggregation and highlight the importance of the local milieu in determining aggregation outcomes.
    DOI:  https://doi.org/10.1016/j.sbi.2026.103355
  5. Commun Chem. 2026 Aug 10. pii: 273. [Epub ahead of print]9(1):
    Liquid-liquid phase-separated tau colocalizes with and stabilizes Aβ oligomers.
    Tina Jacob, Marie P Schützmann, Laurin Gerhards, Laura Hruby, Gabriel Leprivier, Gültekin Tamgüney, Wolfgang Hoyer.
      Protein aggregation is a hallmark of neurodegenerative diseases, where misfolded proteins accumulate into insoluble deposits. Emerging studies indicate that liquid-liquid phase separation (LLPS) may serve as a transient stage in the transition from monomers to amyloid fibrils for several proteins implicated in neurological disorders. In this study, we investigated the interplay between tau and off-pathway oligomers of amyloid-beta (Aβ), the two key proteins in Alzheimer's disease (AD). Our findings demonstrate that tau condensates act as reservoirs for Aβ oligomers under LLPS conditions. Inside the tau condensates, Aβ oligomers reduced tau dynamics and formed discrete puncta, indicating a conducive environment for Aβ oligomer clustering. In contrast, in the absence of LLPS conditions, tau and Aβ oligomers formed solid-like co-aggregates with distinct morphologies. Tau significantly affected the kinetics of Aβ assembly, stabilizing off-pathway oligomers and inhibiting their replacement by amyloid fibrils. Our results highlight interactions between higher-order assemblies of tau and Aβ that may contribute to AD pathology.
    DOI:  https://doi.org/10.1038/s42004-026-02165-6
  6. Nat Neurosci. 2026 Aug 13.
    Dendritic translation and neuroproteasome-mediated degradation of endogenous tau revealed by STARFISH.
    Kalin D Konrad-Vicario, Victoria Paradise, Lara Y Demir, Chi Nguyen, Christopher D Makinson, Zhao Ming, Kapil V Ramachandran.
      In Alzheimer's disease, the protein tau is thought to redistribute from axons to the somatodendritic compartment and form fibrillar aggregates. Although tau aggregation is a hallmark of Alzheimer's disease, the dynamics of its synthesis and degradation are not well characterized. Given that nascent polypeptides are particularly susceptible to misfolding, local control of tau synthesis and degradation may be essential to prevent aggregation. Here we develop STARFISH, a method for visualizing the subcellular site of endogenous mRNA translation in primary neurons and in vivo with single-molecule sensitivity and near-codon resolution, without modifying the nascent polypeptide. Using STARFISH, we show that despite the broad distribution of Mapt mRNA, tau is translated exclusively in neuronal dendrites. About one-third of newly synthesized tau is co-translationally or peri-translationally degraded in dendrites by a neuronal-specific plasma-membrane-associated proteasome, the neuroproteasome. Failure of neuroproteasome-mediated degradation leads to the protein synthesis-dependent accumulation of somatodendritically mislocalized endogenous tau aggregates. These findings define a proteostasis mechanism that counterbalances the constitutive physiological overproduction of tau. We speculate that failure of this proteostasis system contributes to tau aggregation in dendrites in Alzheimer's disease.
    DOI:  https://doi.org/10.1038/s41593-026-02398-7
  7. Cells. 2026 Jul 29. pii: 1365. [Epub ahead of print]15(15):
    The Interactions of Tau, RNA, and Stress Granules in Neurodegenerative Disease: A Comprehensive Review.
    Tristyn N Garza, Jose F Abisambra.
      The discovery of RNA in the late 19th century revolutionized the understanding of cell biology. Subsequent discoveries over the next six decades revealed a key role for RNA in protein synthesis. Nevertheless, today, the mechanisms driving RNA metabolism remain enigmatic. Given its fundamental cellular role, RNA alterations are strongly linked to disease, including devastating neurodegenerative disorders pathologically defined by the accumulation of RNA-binding proteins. For example, the mislocalization of TDP-43, an RNA-binding protein, is a pathological feature of amyotrophic lateral sclerosis and frontotemporal dementia TDP-43. Another group of more than 20 neurodegenerative disorders, called tauopathies, is characterized by the aberrant accumulation of the protein tau. Similarly, the emerging concept that tau binds RNA, facilitating the formation of pathological structures, highlights the importance of RNA stability in tauopathies. However, the dynamics and consequences of RNA-tau interactions remain unclear. This review comprehensively catalogs key findings linking tau, RNA, and stress granules. These findings are important because they could offer novel opportunities to design therapeutic strategies.
    Keywords:  RNA; neurodegeneration; neurodegenerative disease; stress granules; tau
    DOI:  https://doi.org/10.3390/cells15151365
  8. Int J Mol Sci. 2026 Jul 29. pii: 6776. [Epub ahead of print]27(15):
    Protein Self-Interaction in Cellular Function and Network Evolution: Molecular Mechanisms, AI-Driven Insights, and Therapeutic Potentials.
    Yuanxiao Gao, Wenyu Zhang, Guang Hu.
      Protein self-interaction to form homodimers and higher-order homo-oligomers is a ubiquitous phenomenon fundamental to living organisms. Recent structural, system-level, and computational insights reveal that self-interacting proteins dictate the specificity, rewiring, and topological complexity of cellular signaling networks and macromolecular assemblies. Beyond their physiological roles, aberrant or dysregulated homotypic interactions disrupt cellular proteostasis, driving the formation of toxic non-native oligomers, pathological amyloid fibrillization, or aberrant liquid-liquid phase separation transitions linked to neurodegenerative and systemic diseases. This review provides a comprehensive overview of the state-of-the-art experimental methodologies, including proximity labeling, as well as the advanced computational frameworks, such as deep learning architectures and protein language models, used to map the structural dynamics of SIPs. Furthermore, we dissect the evolutionary trajectories of SIPs within protein-protein interaction networks, which are underpinned by dosage-balance constraints, and highlight their diverse functional advantages, ranging from allosteric modulation to biomolecular condensation. Finally, we summarize the molecular mechanisms linking pathological self-associations to human disorders, underscoring the emerging paradigm of targeting homotypic interfaces as a promising frontier for precision therapeutics.
    Keywords:  AlphaFold; allosteric regulation; deep learning; homo-oligomerization; liquid–liquid phase separation; neurodegenerative disease; protein aggregation; protein self-interaction
    DOI:  https://doi.org/10.3390/ijms27156776
  9. Protein Sci. 2026 Sep;35(9): e70762
    Peroxynitrite-induced structural remodeling and aggregation of hemoglobin under nitroxidative stress.
    Shaik Basha, Aradhika Vijeev, Darshan Chikkanayakanahalli Mukunda, Krishna Kishore Mahato.
      Peroxynitrite (PN), generated by the reaction of nitric oxide with superoxide, is a potent reactive nitrogen species (RNS) implicated in nitroxidative protein damage in cardiovascular and neurodegenerative diseases. Hemoglobin (Hb), the principal oxygen-transport protein of erythrocytes, is a key intravascular scavenger and target of PN; however, how controlled PN exposure translates into structural remodeling and aggregation of Hb remains poorly understood. Purified human Hb was exposed to PN across sub-stoichiometric to moderate oxidant excess and characterized using intrinsic fluorescence, UV-visible (UV-vis) spectroscopy, 2,4-dinitrophenylhydrazine (DNPH) carbonyl assay, Thioflavin T (ThT), 8-anilino-1-naphthalenesulfonic acid (ANS), Congo Red (CR), Fourier-transform infrared (FTIR) spectroscopy with Amide I deconvolution, dynamic light scattering (DLS) with zeta potential, x-ray powder diffraction (XRPD), scanning electron microscopy (SEM), atomic force microscopy (AFM), and fluorescence microscopy. At low oxidant loads, PN caused concentration-dependent fluorescence quenching, carbonyl accumulation, and graded UV-visible absorbance increases, consistent with heme-centered oxidation and limited aromatic residue modification. At higher concentrations, Amide I deconvolution revealed collapse of α-helical content from 66.41% to 8.81% and β-sheet enrichment to 71.18%, accompanied by surface charge neutralization, increased hydrodynamic diameter, and enhanced nanoscale roughness. Despite β-sheet accumulation and ThT/CR-positive aggregate formation, XRPD, AFM, SEM, and fluorescence microscopy showed no long-range crystalline order or fibrillar morphology, demonstrating that PN drives Hb toward amorphous and oligomeric assemblies rather than canonical amyloid fibrils. Time-dependent assays at 37°C confirmed that PN modification lowers the nucleation barrier for thermally driven aggregation. These findings define physicochemical thresholds separating protective scavenging from structural destabilization and offer a framework for distinguishing nitroxidative protein aggregation from classical amyloid fibrillation.
    Keywords:  amyloid; hemoglobin; nitroxidative stress; peroxynitrite; protein aggregation
    DOI:  https://doi.org/10.1002/pro.70762
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