bims-amyloi 2026-10-04 papers

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.

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

Front Neurosci. 2026 ;20 1927017

From seeds to symptoms: the molecular landscape of tau seeding in Alzheimer's disease.

Jin Miao, Chunhong Xue, Xuchao Yan, Jianlan Gu, Dandan Chu, Huaichang Sun.

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, pathologically defined by extracellular amyloid-β plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. The Braak staging system established that tau pathology spreads in a stereotypical pattern across the brain, supporting the "prion-like" hypothesis: misfolded tau aggregates serve as seeds, inducing the misfolding and aggregation of normal tau, and thereby driving disease progression along neuroanatomical pathways. In the past 5 years (2021-2026), substantial advances have elucidated the molecular mechanisms underlying tau seeding activity. This review summarizes recent progress in tau seeding research, highlighting both intrinsic and extrinsic regulators of tau prion-like activity. Intrinsic factors include the structural basis of tau strains, MAPT mutations, alternative splicing (3R/4R isoforms), post-translational modifications, and liquid-liquid phase separation. Extrinsic factors encompass cofactors, molecular chaperones, non-coding RNAs, epigenetic mechanisms, environmental exposures, and the emerging concept of trans-seeding by heterologous protein fibrils. We also review therapeutic strategies targeting tau pathology, focusing on their mechanisms and clinical development. Integrating these mechanistic insights and therapeutic advances will inform future research and clinical strategies for AD and related tauopathies.

Keywords: Alzheimer’s disease; extrinsic factors; intrinsic factors; mutation; prion; tau

DOI: https://doi.org/10.3389/fnins.2026.1927017

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

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

Alzheimers Res Ther. 2026 Sep 26. pii: 215. [Epub ahead of print]18(1):

Fecal Aβ and tau aggregates are elevated in cognitive impairment and reveal peripheral proteopathic alterations.

Pelin Özdüzenciler, Laura Müller, Esra Kara, Maria-Christina Weber, Marlene Pils, Fabian Rehn, Oliver Bannach, Gereon R Fink, Dieter Willbold, Michael T Barbe, Oezguer A Onur, Gültekin Tamgüney.

BACKGROUND: Aggregation of amyloid-β (Aβ) and tau is central to Alzheimer's disease (AD) pathogenesis and forms the basis of established cerebrospinal fluid (CSF) and imaging biomarkers. However, increasing evidence suggests that AD involves systemic processes beyond the central nervous system. We previously demonstrated the presence of fecal Aβ aggregates. Here, we assessed the detectability of tau aggregates in human feces and examined the diagnostic value of combined fecal Aβ and tau quantification in cognitive impairment.
METHODS: Using surface-based fluorescence intensity distribution analysis (sFIDA), a single-particle assay selective for aggregated species, we quantified fecal Aβ and tau aggregates in individuals with cognitive impairment (dementia, MCI, SCD) and cognitively normal controls. Associations with CSF biomarkers were assessed, and classification performance was evaluated using cross-validated logistic regression models.
RESULTS: Tau aggregates were detectable in fecal samples. Both fecal Aβ and tau aggregate concentrations were significantly elevated in cognitively impaired individuals and remained independently associated with patient status after adjustment for age and sex. Fecal Aβ aggregates showed inverse associations with CSF tau biomarkers, particularly phosphorylated tau. In cross-validated models, fecal tau aggregates achieved stronger classification performance than fecal Aβ (AUC ~ 0.80 vs. ~ 0.68), and integration of fecal aggregates with demographic predictors improved discrimination to an AUC of 0.90.
CONCLUSIONS: Detection of fecal tau aggregates extends previous observations on fecal Aβ and supports the concept that stool-based aggregate measurements capture systemic aspects of proteopathic biology associated with cognitive impairment. These findings suggest that fecal aggregate quantification may provide a minimally invasive biomarker approach that complements established CNS-based biomarkers and may be useful for patient stratification and monitoring in neurodegenerative disease.

Keywords: Alzheimer’s disease; Amyloid-β aggregates; Fecal biomarkers; Gut-brain axis; Non-invasive diagnostics; Tau aggregates; sFIDA

DOI: https://doi.org/10.1186/s13195-026-02188-0

Adv Sci (Weinh). 2026 Sep 27. e77643

Probing the Energy Landscape of α-Synuclein Amyloid Fibril Formation by Systematic K-to-Q Mutagenesis.

Antonin Kunka, Azad Farzadfard, Jacob Aunstrup Larsen, Rasmus Krogh Norrild, Federica Saraceno, Celia Fricke, Hossein Mohammad-Beigi, Ahmed Sadek, Jonas Folke, Susana Aznar, Alexander K Buell.

Aggregation of α-synuclein (αSyn) is a hallmark of Parkinson's disease, yet its pathological roles remain poorly understood. Elucidating these roles requires detailed knowledge of the free energy landscape of αSyn self-assembly, i.e. the states that can be populated and their mechanisms and rates of interconversion. Here, we quantitatively probe this landscape using systematic mutational analysis, focusing on electrostatic contributions. We designed and produced 41 αSyn variants containing one to six acetyllysine-mimicking (K-Q) mutations to dissect the effects on key assembly pathways, fibril stability, and polymorphism. We derived a quantitative framework for the analysis of mutational effects and used it to isolate general electrostatic from residue-specific effects on de novo αSyn aggregation. We established fibril stability and relative growth rate analysis as indirect biophysical probes of fibril polymorphism and identified K43Q+K45Q and K80Q as mutations with the most significant effect onamyloid formation. Moreover, we demonstrate that a subset of variants, most noticeably K58Q+K60Q, show differential sensitivity toward disease-derived fibril polymorphs in seed amplification assays. Clustering analysis reveals that the mutational effects map onto the structural context of the lysine residues in known αSyn fibril structures. Together, this work provides a scalable, quantitative framework for probing the complex αSyn assembly landscape using mutational analysis.

Keywords: Energy Landscape; IDPs; Mutagenesis; Parkinson's Disease; Polymorph

DOI: https://doi.org/10.1002/advs.77643