bims-amyloi 2026-09-20 papers

Int J Mol Sci. 2026 Aug 22. pii: 7516. [Epub ahead of print]27(17):

Deletion Analysis of Phase Separation, Amyloid Formation and Prion Propagation by the Intrinsically Disordered Region of Yeast Sup35 Protein.

Anastasia V Grizel, Natalia A Gorsheneva, Ismat Jahan Anee, Kristupas Paulius, Konstantin Y Kulichikhin, Aleksandr A Rubel, Yury O Chernoff.

Protein intrinsically disordered regions (IDRs) play important biological roles despite lacking stable structures. IDRs drive the formation of both biomolecular condensates via liquid-liquid phase separation (LLPS) and solid fibrous amyloid aggregates. Amyloids can be pathogenic and may exhibit self-perpetuating (prion) properties. Relationships between LLPS and the amyloid-forming and prion-propagating abilities of IDRs remain poorly understood. The N-proximal IDR of the yeast translation termination factor eRF3 (Sup35) can form both liquid condensates and heritable amyloid-based prions and serves as a powerful model for investigating these phenomena due to the availability of simple phenotypic, cytological and biochemical assays. Deletion analysis demonstrates that the N-proximal prion domain (Sup35N) of Sup35 is sufficient for chaperone-dependent prion propagation and that various regions of this domain show differential impacts on LLPS, amyloid aggregation, and prion inheritance. Specifically, the N-terminal NQ-rich stretch and the region of oligopeptide repeats are the most important contributors to the LLPS and formation of amyloid fibrils, while oligopeptide repeats and the C-terminal region of Sup35N are crucial for prion inheritance. Contrary to previous reports, the NQ-rich stretch is not required for prion formation and inheritance in yeast. Our data indicate that, in addition to amino acid composition, specific sequence motifs control reversible and heritable assemblies of Sup35.

Keywords: IDRs; Saccharomyces cerevisiae; Sup35; [PSI+]; amyloid; osmotic stress; phase separation; prion

DOI: https://doi.org/10.3390/ijms27177516

Protein Sci. 2026 10;35(10): e70782

Full-length brain-derived α-synuclein fibril models reveal fuzzy-coat control of peptide recognition.

Carlos Pintado-Grima, Oriol Bárcenas, Giulio Tesei, F Emil Thomasen, Kresten Lindorff-Larsen, Salvador Ventura.

α-Synuclein (aSyn) fibrils in Parkinson's disease are generally represented by their ordered cross-β cores, although nearly half of the protein remains disordered in the fibrillar state. The unresolved N- and C-terminal segments form a fuzzy coat that is expected to shape the surface encountered by molecular partners. Here, we reconstructed full-length, brain-derived aSyn Lewy-fold fibrils by extending a patient-derived cryo-EM core spanning residues 31-100, with disordered termini, and sampling the resulting assemblies with the CALVADOS coarse-grained force field. The acidic C-terminal tails established recurrent, transient contacts with solvent-exposed core motifs, especially β5/P2 and β9/P3, generating a dynamic surface in which aggregation-prone ladders are intermittently shielded rather than permanently buried. Simulations with two experimentally validated aSyn-binding peptides, PSMα3 and LL-37, show that peptide recognition follows a two-step process. Cationic peptides are first retained by the anionic fuzzy coat and subsequently engage exposed hydrophobic/electrostatic hotspots on the structured core. PSMα3 variants and LL-37 controls support the importance of positive charge for capture, peptide flexibility for multivalent engagement, and the full-length fibril architecture for persistent binding. These results present a mechanistic model in which selectivity for aggregated aSyn arises from an emergent mesoscale interface combining a polyelectrolyte brush with recurrent core hotspots. Together, these results establish full-length, brain-derived fibril ensembles as a practical framework for understanding ligand recognition at amyloid surfaces.

Keywords: CALVADOS; Parkinson's disease; amyloid fibrils; fuzzy coat; intrinsically disordered regions; molecular dynamics simulations; peptide binding; α‐synuclein

DOI: https://doi.org/10.1002/pro.70782

Mol Neurodegener Adv. 2026 ;2(1): 38

Targeting protein aggregate co-pathologies in neurodegeneration: a viable therapeutic strategy?

Silas A Buck, Sidharth S Madhavan, Laurie H Sanders.

Many neurodegenerative diseases are characterized by pathological protein aggregation in the brain. Alzheimer's disease displays amyloid-β and tau inclusions in the form of amyloid-β plaques and tau neurofibrillary tangles. Synucleinopathies comprise Parkinson's disease and Dementia with Lewy bodies, which are classified by α-synuclein depositions in the form of Lewy bodies, as well as multiple system atrophy, which displays glial cytoplasmic α-synuclein inclusions. Tar DNA binding protein 43 (TDP-43) inclusions are observed in amyotrophic lateral sclerosis and frontotemporal lobar dementia with TDP-43 inclusions. A separate subgroup of frontotemporal lobar dementias, including Pick's disease, progressive supranuclear palsy and corticobasal degeneration, are characterized by disease-specific patterns of tau pathology and are termed primary tauopathies. Despite these classifications, it is not often appreciated that neurodegenerative diseases commonly display amyloid-β, tau, α-synuclein, and/or TDP-43 co-pathologies not typically associated with that specific disease's pathophysiology. Additionally, in vitro and in vivo proteinopathy models show interactions between pathological forms of these proteins that increase protein aggregation and neurotoxicity, suggesting distinct mechanisms underlying co-pathologies that play a significant role in neurodegeneration. In this review, we describe the frequency of protein co-pathologies across neurodegenerative diseases and preclinical work demonstrating pathological protein synergies that exacerbate protein aggregation and toxicity. We also discuss granulovacuolar degeneration bodies, proteolytically active lysosomal structures that are induced by either pathological tau or α-synuclein accumulation, as an example of a shared cellular response to, and link between, distinct protein pathologies. Finally, we highlight interventional clinical trials which target multiple pathologies and/or specifically target co-pathologies in neurodegenerative diseases, noting that current preclinical and clinical research is limited and this line of investigation should be pursued more vigorously. In all, we find that protein co-pathologies are frequently observed in the brains of common neurodegenerative diseases and serve as important future therapeutic targets for combatting neurodegeneration across clinically distinct diseases.
Graphical abstract:

Keywords: Alzheimer’s disease; Amyloid; Amyotrophic lateral sclerosis; Co-pathology; Granulovacuolar degeneration bodies; Lewy body disease; Synuclein; TDP-43; Tau; Tauopathy

DOI: https://doi.org/10.1186/s44477-026-00047-8

Adv Sci (Weinh). 2026 Sep 16. e77822

Temporal Trajectories of the Tau Aggregate Interactome Reveal Stage-Specific Vulnerabilities in Alzheimer's Disease.

Dorothea Böken, Paula Beltran Lobo, Yunzhao Wu, Lyla A Rowe, Emre Fertan, Cara L Croft, Maria Jimenez-Sanchez, Dezerae Cox, David Klenerman.

Tau aggregation is a central pathological feature of Alzheimer's disease, yet how different forms of tau-ranging from monomers to small soluble aggregates and mature fibrils-interact with the cellular environment remains poorly understood. Here, we combine immunoaffinity proteomics with single-molecule techniques and super-resolution microscopy to systematically map the tau interactome across defined aggregation states, spanning monomeric tau, nanoscopic soluble aggregates, and fibrillar species. Using post-mortem Alzheimer's disease brain tissue, we identify distinct functional modules associated with different aggregation states: while proteostasis factors and immune-related proteins preferentially associate with nanoscopic aggregates (oligomers), cytoskeletal, metabolic, and RNA-binding proteins are enriched for mature fibrillar tau. Single-molecule microscopy directly confirms this conformation-dependent recruitment for key interactors including Hsp70-2, ENO1, hnRNPA1, APP, EAAT4, and ubiquitin. A primary-neuron system with accelerated tau aggregation is used to model these findings in a controlled system, showing striking similarities to the brain samples. Finally, pseudotime analysis reconstructs a progressive remodelling of the tau interactome across disease progression, revealing stage-specific pathway vulnerabilities. Together, these results establish a temporally resolved framework for tau pathology shaped by protein interactions and identify potential therapeutic intervention points for investigation across stages of disease.

Keywords: Alzheimer's disease; Tau; interactome; proteomics; single‐molecule

DOI: https://doi.org/10.1002/advs.77822

Mol Neurodegener Adv. 2026 ;2(1): 37

Autophagy-lysosomal pathway in neurodegeneration.

Samantha R McDonough, Aditya K Rao, Jacqueline M McAleer, Bergan M Babrowicz, Manu Sharma.

Autophagy-Lysosomal Pathway (ALP) dysfunction has emerged as a prominent mechanism underlying neurodegenerative disease. Given its central role in facilitating cellular clearance of misfolded proteins, damaged organelles and other cellular debris, the ALP is vital for cellular health and survival. In mature neurons, whose post-mitotic state renders them unable to dilute such materials through cell division, this waste removal pathway takes on an even greater importance. It is therefore unsurprising that ALP dysfunction is increasingly implicated in the context of age-associated neurodegenerative disease, where impaired proteostasis and pathological protein aggregation are common hallmarks. The focus of this review is how dysregulation of ALP-associated processes, including autophagic flux, chaperone-mediated autophagy, endolysosomal trafficking, lysosomal pH and ion balance, and lysosomal metabolic signaling, is implicated in both the pathogenesis and progression of neurodegenerative diseases, with an emphasis on Alzheimer's disease and Parkinson's disease. A more detailed understanding of how these processes, both independently and cooperatively, contribute to the development and progression of neurodegenerative disease will improve our understanding of these debilitating disorders and inform the development of ALP-targeted therapeutic strategies.

Keywords: Alzheimer’s disease; Autophagy; Lysosome; Neurodegeneration; Parkinson’s disease; Proteostasis

DOI: https://doi.org/10.1186/s44477-026-00041-0