bims-proned 2026-06-28 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–06–28
fifteen papers selected by
Verena Kohler, Umeå University

Raman Spectroscopy for Probing Pathological Protein Aggregates: Potential and Perspectives for Advanced Diagnostic Applications.
Divergent effects of pathological α-synuclein truncations and mutations on phase separation.
Tightly Knotted Enzymes Inhibit Protein-Protein Aggregation.
Isoform-specific steric zippers drive aberrant assembly and mislocalization of shortened TDP-43.
A α-synuclein aggregation inhibitor exerts neuroprotective effects via mitochondrial resilience in Parkinson's disease.
Tau Disaggregation by a CNS-Permeable Small Molecule Reduces Fibril and Oligomer Burden and Preserves Proteostasis and Behavior.
Aminochrome-Induced Disruption of Autophagosome-Lysosome Fusion: Implications for Protein Aggregation in Parkinson's Disease.
IRE1 regulates the proteostasis of TDP-43/TARDBP in ALS/FTD through ribosome-associated quality control.
Small bites for big problems: stepwise aggregate degradation by autophagy.
Temperature-Dependent Dynamics of Aβ42 and α-Synuclein Monomers and Early Oligomerization of Aβ42: Shared Residues Mediate Intra- and Intermolecular β-Sheets.
The Diagnostic and Therapeutic Value of Micro-RNA in Parkinson's Disease.
Biophysical and Computational Insights into Alpha-1 Antitrypsin Aggregation and Its Inhibition by Natural Polyphenols.
Profiling Protein Aggregate Size Using Single-Molecule Array Technology.
Role of α-Synuclein in the Prefrontal Cortex: From Physiological Synaptic Modulation to Synaptic Failure in Parkinson's Disease.
Elimination of tau tangles and soluble aggregates with the small molecule ACI-16664 prevents neurodegeneration in vivo.

Int J Mol Sci. 2026 Jun 19. pii: 5550. [Epub ahead of print]27(12):

Raman Spectroscopy for Probing Pathological Protein Aggregates: Potential and Perspectives for Advanced Diagnostic Applications.

Alice Gualerzi, Valentina Mangolini, Luana Forleo, Chiara Cabrini, Silvia Picciolini, Marzia Bedoni.

  Parkinson's disease and Alzheimer's disease are currently classified as a major global health burden, sharing a defining pathological hallmark represented by insoluble protein aggregates of α-synuclein (α-syn) and amyloid-β (Aβ), respectively. A defining characteristic of all amyloids is a highly ordered, unbranched filamentous morphology, where individual β-strands align perpendicularly to the filament axis. Despite recent technological advances, direct observation of protein conformational changes and amyloid formation in biological samples remains a challenge as well as the quantification of pathological aggregates in liquid biopsies. This review critically recapitulates the major advances in the application of Raman spectroscopy (RS) and surface-enhanced Raman spectroscopy (SERS) in the investigation of pathological protein aggregates in neurological disorders, with a focus on α-syn and Aβ. We discuss both in vitro structural characterization and the applications to biological and clinical samples, outlining the main challenges for clinical translation, including the need for standardized protocols. Recent achievements in the use of RS and SERS on liquid biopsies and other clinical samples are paving the way for further implementation of Raman-based approaches for the diagnosis of neurodegenerative disorders.

Keywords:  Raman spectroscopy; amyloid-β; biomarkers; diagnosis; neurodegenerative diseases; protein aggregation; surface-enhanced Raman spectroscopy; α-synuclein

DOI:  https://doi.org/10.3390/ijms27125550
Nat Commun. 2026 Jun 25.

Divergent effects of pathological α-synuclein truncations and mutations on phase separation.

Soumik Ray, Antonin Kunka, Sophie Hertel, Cecilia Chiodaroli, Katharina Schott, Azad Farzadfard, Kristina Mojtic, Louise Kjær Klausen, Frederik Ravnkilde Marlet, Céline Galvagnion, Alexander K Buell.

Phase separated condensates of α-synuclein (α-Syn) accelerate amyloid fibril formation, a process implicated in Parkinson's disease pathogenesis. Yet, the precise effects of pathologically relevant α-Syn sequence modifications on this process remain unclear. Here, we show that sequence truncations exert the strongest influence on condensate thermodynamics, material properties, and amyloid aggregation, whereas familial point mutations impart minimal effects. Among the tested familial variants (A30P, H50Q, G51D and A53T), only G51D forms condensates that show a reduced propensity for amyloid fibril formation. Truncated variants undergo rapid gelation and form amyloid fibrils almost immediately. Extending our study to multicomponent systems where α-Syn is a client, we show that α-Syn can dissolve DNA-peptide coacervates or assemble into Pickering clusters on condensate surfaces-regulating condensate fusion and nucleic acid partitioning. These functions depend on the acidic C-terminal domain of α-Syn. Together, our results show disease-relevant modifications can modulate α-Syn phase behavior, both in pathological and physiological contexts.

DOI: https://doi.org/10.1038/s41467-026-74627-3
bioRxiv. 2026 Jun 13. pii: 2026.06.12.731949. [Epub ahead of print]

Tightly Knotted Enzymes Inhibit Protein-Protein Aggregation.

Susmita Sarkar, Hemanth Mandya Nagaiah, Michael L Klein, Vincenzo Carnevale.

Neurodegenerative diseases are closely linked to aberrant protein aggregation arising from failures in cellular proteostasis, yet the physical determinants governing transitions between soluble states, liquid-liquid phase separation (LLPS), and aggregation remain incompletely understood. Here, we investigate how protein backbone topology influences phase behavior using ubiquitin C-terminal hydrolase L1 (UCH-L1), a highly neuron-enriched deubiquitinase in the ubiquitin-proteasome system harboring a rare, evolutionarily conserved knotted backbone topology, and its Parkinson's disease-associated I93M mutant. Through multiscale molecular dynamics (MD) simulations of single-chain and multichain systems, we show that knot integrity acts as a conformational constraint that limits access to expanded states, and suppresses LLPS propensity. Destabilization of the native knotted ensemble in I93M reshapes the conformational ensemble, enhancing intermolecular contacts, strengthening hydrophobic interaction, and reducing solvation penalties, thereby stabilizing protein-rich phases. Within condensates, these changes lead to persistent interchain contacts, increased topological entanglement, and slower relaxation dynamics, indicative of a transition toward viscoelastic assemblies, whereas intact topology maintains dynamic, liquid-like behavior. Our results identify topological integrity as a key physical determinant of protein phase behavior and establish a mechanistic link between topological stability and condensate material properties, with implications for aggregation-associated neurodegeneration.

DOI: https://doi.org/10.64898/2026.06.12.731949
Sci Adv. 2026 Jun 26. 12(26): eady0256

Isoform-specific steric zippers drive aberrant assembly and mislocalization of shortened TDP-43.

Katie E Copley, Megan M Dykstra, Morgan R Miller, Miriam Linsenmeier, Longsheng Lai, Yuanhang Wang, Yi-Wei Chang, Sami J Barmada, James Shorter.

Prion-like domain (PrLD)-mediated aggregation and concomitant dysfunction of the essential RNA-binding protein transactive response (TAR) DNA-binding protein of 43 kilodaltons (TDP-43) is a common feature of multiple debilitating neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). However, shortened TDP-43 (sTDP-43) splice isoforms where the PrLD is largely replaced by an 18-residue carboxyl-terminal tail also contribute to ALS pathophysiology and are enriched in motor neurons. Curiously, despite lacking most of the PrLD, sTDP-43 exhibits pronounced insolubility in cells and tissue of patients with ALS. Here, we establish that the short, isoform-specific carboxyl-terminal tail of sTDP-43 confers high aggregation propensity, which is encoded by two clusters of steric zippers, and can be mitigated by short RNA chaperones. Disrupting these zippers enhances sTDP-43 solubility at the pure protein level and in neurons. Notably, these steric zippers, rather than a predicted nuclear export signal in the carboxyl-terminal tail, drive cytoplasmic mislocalization and aggregation of sTDP-43 in neurons. Thus, we define the sequence-encoded determinants of aberrant sTDP-43 assembly and provide mechanistic insights into sTDP-43 disease pathology.

DOI: https://doi.org/10.1126/sciadv.ady0256
J Adv Res. 2026 Jun 22. pii: S2090-1232(26)00508-4. [Epub ahead of print]

A α-synuclein aggregation inhibitor exerts neuroprotective effects via mitochondrial resilience in Parkinson's disease.

Ye Peng, Junrui Ye, Hongyun Wang, Shasha Wang, Wenfei Wang, Xu Yan, Shifeng Chu, Ruifang Zheng, Zhao Zhang, Naihong Chen.

   INTRODUCTION: The pathogenesis of Parkinson's disease (PD) is driven by a vicious cycle of α-synuclein (α-Syn) aggregation and mitochondrial collapse. Breaking this pathogenic loop requires disease-modifying therapeutics capable of destabilizing the toxic structural core of α-Syn while simultaneously rescuing bioenergetic failure, highlighting an urgent need for novel dual-action neuroprotective agents.
OBJECTIVES: To identify and characterize A14, a novel small-molecule modulator, and evaluate its dual capacity to inhibit α-Syn fibrillization and mitigate downstream mitochondrial deficits in PD.
METHODS: Structure-based virtual screening was employed to identify A14 as a targeted inhibitor of the α-Syn fibril β-sheet interface. Its biophysical mechanisms were elucidated using multi-dimensional structural assays. In cellular models and A53T α-Syn transgenic mice, systematically evaluated the therapeutic efficacy, wherein transcriptomics and transmission electron microscopy were adopted to detect mitochondrial integrity, and functional magnetic resonance imaging (fMRI) together with electrophysiology were utilized for the assessment of nigral circuit function.
RESULTS: A14 binds the β-sheet core of α-Syn fibrils with high affinity (Kd = 27.9 ± 2.16 nM), significantly reducing β-sheet content from 21.4% to 9.3% and redirecting the aggregation trajectory into small (< 20 nm), protease-sensitive intermediates. In neuronal models, A14 robustly reduced intracellular α-Syn inclusions via direct biophysical modulation, independent of major proteostasis pathways. In vivo, A14 disrupted the pathological interaction between α-Syn and mitochondria, rescuing cristae ultrastructure, oxidative phosphorylation, and overall bioenergetics. This coordinated restoration of proteostasis and mitochondrial function prevented dopaminergic neuron loss, normalized cortico-basal ganglia-nigral functional connectivity, and significantly ameliorated motor deficits in A53T transgenic mice.
CONCLUSIONS: Our findings demonstrate that the A14 engages complementary mechanisms to inhibit α-Syn aggregation and rescue mitochondrial deficits. This dual action stabilizes proteostasis and sustains mitochondrial functionality, nominating A14 as a promising therapeutic candidate for the treatment of PD.

Keywords:  Mitochondria dysfunction; Parkinson’s disease; Small molecule; α-Synuclein

DOI:  https://doi.org/10.1016/j.jare.2026.06.026
bioRxiv. 2026 Jun 12. pii: 2026.06.09.731185. [Epub ahead of print]

Tau Disaggregation by a CNS-Permeable Small Molecule Reduces Fibril and Oligomer Burden and Preserves Proteostasis and Behavior.

N Mostowfi, R Foreman, J Wang, R Khoury, A Albanese, Q L Ma, W Cohn, G Petzinger, M Jakowec, S K Ahmed, P M Seidler.

Pathological tau aggregates drive neuronal dysfunction in Alzheimer's disease (AD) and related tauopathies, yet no approved therapy eliminates existing tau neurofibrillary tangles. Here, we report the development of a coumarin-based small-molecule series that disaggregates tau fibrils and oligomers through a stacking-driven co-assembly mechanism. Structure-activity relationships identified PT-13 as a lead compound that inhibits tau seeding by AD brain-derived matter and reduces aggregate burden measured across both fibrillar and oligomeric tau species. Mechanistic studies demonstrate that disaggregation does not generate soluble oligomeric intermediates, addressing a central question in the field. PT-13 is brain-penetrant and well tolerated in vivo. In a tauopathy mouse model, PT-13 treatment reduces tau pathology while preserving behavioral function, proteasome capacity, and synaptic integrity. These findings establish small-molecule tau disaggregation as a viable therapeutic strategy and provide a molecular framework for the design of aggregate-directed therapeutics in neurodegeneration.

DOI: https://doi.org/10.64898/2026.06.09.731185
Antioxidants (Basel). 2026 Jun 10. pii: 739. [Epub ahead of print]15(6):

Aminochrome-Induced Disruption of Autophagosome-Lysosome Fusion: Implications for Protein Aggregation in Parkinson's Disease.

Andrea Briceño, Cipriano Núñez, Karina Cortés, Patricia Pallacán, Nicole Salinas, Carola Millán, Juan F Vivanco, Nelson Caro, Juan Segura-Aguilar, Irmgard B Paris.

  Aminochrome, an endogenous neurotoxin, has been implicated in the loss of neuromelanin-containing dopaminergic neurons in the nigrostriatal system in Parkinson's disease. Although aminochrome-induced oxidative stress and its inhibitory effects on microtubule polymerization are well documented, its impact on protein aggregation remains poorly understood. The aim of this research was to evaluate the effects of aminochrome on protein aggregate accumulation in SH-SY5Y cells differentiated into dopaminergic neurons. While the role of aminochrome in autophagy has been described, its direct effect on autophagosome-lysosome fusion has not been studied. Our findings reveal that aminochrome, like vinblastine, delays autophagosome-lysosome fusion and induces cell death. This inhibitory effect was also observed in the presence of autophagy inducers, which partially attenuated aminochrome-induced cell death. Under these conditions of disruptions in autophagosome-lysosome fusion, a marked accumulation of perinuclear vimentin and ubiquitin aggregates was observed. Aminochrome also increased colocalization between vimentin and ubiquitin. Interestingly, ubiquitin aggregates were also detected within the nucleus. These findings suggest that aminochrome-induced disruption of the microtubule network, particularly its impairment of autophagosome-lysosome fusion and promotion of protein aggregation, may represent a critical mechanism leading to cell death. In addition, inhibition of autophagosome-lysosome fusion may contribute to the accumulation of perinuclear and nuclear protein aggregates, which may be associated with either toxic or non-toxic pathways. Our findings underscore the therapeutic potential of targeting both microtubule stabilization and proteostasis pathways, including autophagy and the ubiquitin-proteasome system (UPS), in Parkinson's disease, highlighting the need for further research into nuclear proteotoxicity mechanisms.

Keywords:  Parkinson’s disease; aminochrome; autophagy; microtubules; protein aggregation; ubiquitin; vimentin

DOI:  https://doi.org/10.3390/antiox15060739
Proc Natl Acad Sci U S A. 2026 Jun 30. 123(26): e2610001123

IRE1 regulates the proteostasis of TDP-43/TARDBP in ALS/FTD through ribosome-associated quality control.

Dongyue Liu, Yu Li, Shuai Huang, Yufang Xu, Lei Sun, Wen Li, Cahir J O'Kane, David C Rubinsztein, Bingwei Lu, Shuangxi Li.

  Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders characterized by motor neuron degeneration, leading to muscle weakness, atrophy, and cognitive impairments. A defining pathological hallmark of ALS/FTD is the cytosolic mislocalization and accumulation of TAR DNA-binding protein 43 (TDP-43), highlighting its critical role in ALS pathogenesis. However, the molecular mechanisms underlying TDP-43 proteostasis remain poorly understood. Through a genetic screening approach, we identify inositol-requiring enzyme 1 (IRE1), an endoplasmic reticulum-resident transmembrane protein, as a potent suppressor of TDP-43 protein levels. Furthermore, we show that ribosome-associated quality control (RQC) factors play a crucial role in regulating TDP-43 proteostasis and cellular toxicity. Activation of the RQC pathway prevents excessive accumulation of TDP-43 and associated toxicity. Mechanistically, our findings suggest that IRE1 regulates TDP-43 protein level by promoting the degradation of aberrant TDP-43 translation product through the RQC pathway. IRE1 acts canonically to enhance the transcription of the RQC core component Clbn/NEMF and noncanonically to physically interact with Clbn/NEMF, thereby ameliorating TDP-43-induced proteotoxicity. Moreover, ectopic expression or pharmacological activation of IRE1 alleviates TDP-43 pathology and restores cognitive function in the TDP-43 A315T ALS mouse models. Collectively, our study identifies a role for IRE1 in the translational quality control of TDP-43 and establishes its potential as a therapeutic target for ALS/FTD.

Keywords:  IRE1; TDP-43/TARDBP; ribosome-associated quality control (RQC)

DOI:  https://doi.org/10.1073/pnas.2610001123
Biochem Soc Trans. 2026 Jun 24. 54(6): 803-814

Small bites for big problems: stepwise aggregate degradation by autophagy.

Mark S Hipp, Mario Mauthe.

  Protein aggregates are a pathological hallmark of diverse disorders, including many neurodegenerative diseases, but also cardiometabolic disease and cancer. While the ubiquitin-proteasome system efficiently removes many soluble misfolded proteins, large or persistent assemblies often require the autophagy-lysosome pathway for their degradation. In the present mini-review, we summarize our knowledge of aggrephagy, the selective clearance of protein aggregates by autophagy, and discuss two recent manuscripts that argue that some aggregates must be primed for autophagosomal degradation, through chaperone-mediated remodeling. Aggrephagy substrates are defined by aggregate architecture, biophysical state, surface accessibility, and the physical constraints of membrane capture. These features help to explain why recruitment of selective autophagy receptors is necessary yet insufficient for clearance. Receptor clustering is required to concentrate early autophagy factors to establish initiation hubs, but successful degradation often requires upstream generation of smaller 'aggrephagy-competent' cargo units, which contain autophagy receptor clusters that successfully initiate autophagosome formation. Recent work supports a model in which larger aggregates are cleared through stepwise degradation enabled by prior remodeling steps that involve p97/VCP-driven disintegration or a chaperone module (DNAJB6-HSP70-HSP110) cooperating with the proteasomal 19S regulatory particle.

Keywords:  autophagy; cellular protein quality control; molecular chaperones; piecemeal; selective autophagy receptors

DOI:  https://doi.org/10.1042/BST20250460
ACS Chem Neurosci. 2026 Jun 23.

Temperature-Dependent Dynamics of Aβ42 and α-Synuclein Monomers and Early Oligomerization of Aβ42: Shared Residues Mediate Intra- and Intermolecular β-Sheets.

Gabriel F Martins, Cristiano Rocha, Nuno Galamba.

  We used molecular dynamics simulations to investigate how temperature modulates hydrophobic interactions and β-sheet formation in the CHARMM36m model of intrinsically disordered proteins, focusing on a monomer of amyloid-beta (Aβ42) and α-synuclein, as well as a dimer and tetramer of Aβ42. For the isolated monomers, increasing temperature leads to an increase in intramolecular contacts, promoting hydrogen bonding and secondary-structure reorganization toward β-sheet and turn motifs. Analysis of the dimer and tetramer of Aβ42 reveals increased conformational heterogeneity at high temperatures, suggesting a smaller-than-expected configurational entropy penalty upon association. Thus, whereas monomers undergo temperature-induced compaction, enhancing intramolecular interactions, including the formation of β-sheets, in the dimer and tetramer, hydrophobic stabilization is redirected toward aggregation, promoting cross-β-sheet formation, peptide elongation, and the emergence of spherical conformations. Notably, the residues that stabilize intramolecular β-sheets in the monomer (approximately sequences 16-22 and 29-36) largely overlap with those that form cross-β-sheet motifs in the aggregates, suggesting that intramolecular β-sheet formation is intrinsically linked to aggregation propensity. These results, in close agreement with earlier NMR measurements of the monomer and protofibrils, reveal a competition between intra- and intermolecular hydrophobic interactions, with intermolecular interactions ultimately becoming more favorable than the intramolecular interactions that stabilize monomer solvation.

Keywords:  hydrophobic effect; molecular dynamics; neurodegenerative diseases; oligomerization

DOI:  https://doi.org/10.1021/acschemneuro.6c00242
Cell Mol Neurobiol. 2026 Jun 26.

The Diagnostic and Therapeutic Value of Micro-RNA in Parkinson's Disease.

Guo-Liang Lin, Yue Wang, Bi-Huan Cheng.

  The pathogenesis of Parkinson's disease (PD) remains incompletely understood, and effective early diagnostic biomarkers and disease-modifying therapies are lacking. MicroRNAs (miRNAs), a class of small non-coding RNAs, have emerged as critical regulators of gene expression involved in key pathological processes of PD, including neuronal apoptosis, mitochondrial dysfunction, oxidative stress, and α-synuclein (α-syn) aggregation. Recent evidence suggests that dysregulated miRNAs expression contributes significantly to PD progression and may serve as minimally invasive biomarkers for early diagnosis. Furthermore, miRNA-based therapeutic strategies offer promising avenues for targeting disease-related molecular pathways. This review summarizes the mechanistic roles of miRNAs in PD pathogenesis and highlights their potential clinical applications in diagnosis and therapy.

Keywords:  Biomarkers; Epigenetics; Micro-RNA (miRNA); Parkinson's disease (PD); α-synuclein (α-syn)

DOI:  https://doi.org/10.1007/s10571-026-01767-x
Biomedicines. 2026 Jun 09. pii: 1310. [Epub ahead of print]14(6):

Biophysical and Computational Insights into Alpha-1 Antitrypsin Aggregation and Its Inhibition by Natural Polyphenols.

Tarique Sarwar, Ahmed Abdur Rehman, Hussain Arif, Wanian M Alwanian, Hajed Obaid A Alharbi, Arshad Husain Rahmani.

  Background/Objectives: Protein misfolding and amyloid fibril formation underlie several degenerative diseases, including Alzheimer's disease and Parkinson's disease. Alpha-1 antitrypsin (A1AT), a serpin protein, is particularly prone to misfolding, with polymerization and aggregation implicated in alpha-1 antitrypsin deficiency and associated hepatic and pulmonary disorders. In this study, we examined the structural changes in A1AT induced by the fluorinated alcohol, trifluoroethanol (TFE), and assessed the inhibitory effects of two natural polyphenols, amentoflavone (AMF) and theaflavin (TF), on aggregation and fibril formation. Methods: A library of selected phytocompounds was virtually screened against the crystal structure of A1AT (PDB 3NE4) using AutoDock Vina to elucidate their binding affinity towards it. Based on binding affinities, two compounds, AMF and TF, were selected for further studies. Protein aggregation was induced with TFE, and the protective effects of AMF and TF were evaluated using protease inhibitory activity, intrinsic fluorescence, turbidity, Rayleigh scattering, ANS fluorescence, and ThT fluorescence assays. Furthermore, 100 ns molecular dynamics simulation and MM-PBSA calculations were performed to assess the stability and binding interactions of the A1AT-ligand complexes. Results: Pre-treatment of A1AT with AMF or TF significantly inhibited TFE-induced aggregation in a dose-dependent manner, with AMF being consistently more effective. ThT fluorescence analysis revealed a ~60-65% decrease in aggregate formation upon treatment with polyphenols, with IC50 values estimated at ~40 µM for AMF and ~50 µM for TF, both of which are statistically significant. Molecular docking and 100 ns molecular dynamics simulation also revealed stable A1AT-polyphenol interactions, with AMF exhibiting greater binding affinity and greater attenuation of solvent-induced conformational perturbation. Conclusions: Collectively, our findings show that TFE causes A1AT misfolding via a molten globule-like intermediate, resulting in fibril formation at 30-40% TFE, and natural polyphenols AMF and TF inhibited aggregation in a concentration-dependent manner. These observations suggest the potential of AMF and TF as lead scaffolds for anti-aggregation strategies, as modulators of amyloidogenic processes.

Keywords:  aggregation; alpha-1-antitrypsin; amentoflavone; amyloid fibrils; inhibition; molecular dynamics simulation; molten globule; polyphenols; protein; theaflavin

DOI:  https://doi.org/10.3390/biomedicines14061310
Anal Chem. 2026 Jun 25.

Profiling Protein Aggregate Size Using Single-Molecule Array Technology.

Dorothea Böken, Yunzhao Wu, Jianli Zhang, Zengjie Xia, Paula Beltran-Lobo, Cara L Croft, Savinu Weerasekera, Amanda Heslegrave, Henrik Zetterberg, Ashvini Keshavan, Jonathan M Schott, Maria Jimenez-Sanchez, David C Duffy, David Klenerman.

Protein aggregation is a central feature of many neurodegenerative diseases, yet methods to characterize aggregate size in complex biological samples remain limited. Here, we show that fluorescence intensity from individual single-molecule array (Simoa) microwells encodes size-dependent information beyond conventional digital quantification. Using defined synthetic tau assemblies, we establish that increasing aggregate size produces higher microwell brightness. Applying this technique to human brain homogenate reveals a shift toward larger tau aggregates in Alzheimer's disease compared to age-matched controls, in agreement with orthogonal measurements by single-molecule super-resolution microscopy. Brightness profiling further captures time-dependent aggregate size increase in a neuronal cell model, demonstrating sensitivity to dynamic changes in aggregation. Although resolution is limited between similarly sized small species, Simoa brightness robustly reports population-level shifts in aggregate size distributions. These findings repurpose a widely used ultrasensitive detection platform to provide high-throughput structural as well as quantitative insight into protein aggregation in biological systems.

DOI: https://doi.org/10.1021/acs.analchem.6c03315
Biomedicines. 2026 Jun 20. pii: 1394. [Epub ahead of print]14(6):

Role of α-Synuclein in the Prefrontal Cortex: From Physiological Synaptic Modulation to Synaptic Failure in Parkinson's Disease.

Uxia Argibay, María Sancho-Alonso, Claudia Yanes-Castilla, Judith Jericó-Escolar, Verónica Paz, Esther Ruiz-Bronchal, Lluis Miquel-Rio, Analia Bortolozzi.

  α-Synuclein (α-Syn) is a key presynaptic protein, primarily known for its role in the pathogenesis of Parkinson's disease (PD) and other synucleinopathies, including dementia with Lewy bodies (DLB). Although much of the research has focused on the nigrostriatal dopamine (DA) pathway, there is growing recognition that the accumulation of misfolded α-Syn in the prefrontal cortex (PFC) is a critical driver of non-motor symptoms and cognitive deficits in PD and DLB. This review examines the dual role of α-Syn in the PFC circuitry, initially exploring its regulation of synaptic vesicle (SV) dynamics and recycling to maintain stable neurotransmission. We highlight its contribution to the modulation of glutamatergic (Glu) and GABAergic (γ-aminobutyric acid, GABA) synapses, which ensures the functional excitatory/inhibitory (E/I) balance of prefrontal circuits. Conversely, in PD and DLB, the transition of functional α-Syn monomers to pathological oligomers triggers a cascade of synaptic failures. We analyze how α-Syn aggregation causes pathology in dendritic spines, leads to a progressive reduction in the density of synaptic markers, and impairs cortical plasticity. Synthesizing evidence from neuroimaging studies, post-mortem human cortical samples, and animal models, this review emphasizes the PFC as a vulnerable brain region where α-Syn-mediated synaptic dysfunction translates into cognitive and emotional deficits. Deciphering these early synaptic alterations is essential for developing neuroprotective strategies that preserve cortical function in PD and DLB.

Keywords:  GABA; Parkinson’s disease; dementia with Lewy bodies; glutamate; prefrontal cortex; synaptic plasticity; α-Synuclein

DOI:  https://doi.org/10.3390/biomedicines14061394
Alzheimers Dement. 2026 Jul;22(7): e71572

Elimination of tau tangles and soluble aggregates with the small molecule ACI-16664 prevents neurodegeneration in vivo.

Nicolas Preitner, Véronique Dehlinger, Patrick Rodriguez, Kerstin Fabbri, Yvan Varisco, Matteo Pigni, Alessandra Lovison, Lucas Münzenmaier, Kasia Piorkowska, Aline Fuchs, Nadine Ait-Bouziad, Nicolas Fournier, Sandra Jepaul, Jérôme Molette, Emanuele Gabellieri, Vincent Darmency, Sonia Poli, Andrea Pfeifer, Marie Kosco-Vilbois, Francesca Capotosti.

   INTRODUCTION: Pathological tau aggregates are key therapeutic targets in Alzheimer's disease (AD), but current approaches face limitations including poor intracellular penetration, lack of selectivity for aggregated over physiological tau, or reliance on invasive administration.
METHODS: ACI-16664, an orally available brain penetrant tau aggregation inhibitor, was identified through medicinal chemistry optimization of the Morphomer library and characterized using biochemical assays, neuronal cultures, and the Tg4510 tauopathy mouse model.
RESULTS: ACI-16664 selectively bound aggregated tau with high apparent affinity, destabilized its β-sheet structures, blocked intracellular seeding by both soluble and insoluble tau, and prevented tau-induced neurotoxicity. In Tg4510 mice, ACI-16664 reduced both soluble tau aggregates and tangles, and prevented neuronal loss, synaptic degeneration, and cortical atrophy.
DISCUSSION: These findings demonstrate the therapeutic value of targeting tau aggregation across its diverse pathological forms and cellular compartments, supporting the potential of this approach to benefit patients with AD and other tauopathies across disease stages.

Keywords:  Alzheimer's disease; cortical atrophy; neurodegeneration; neurofibrillary tangles; small molecule; soluble high‐molecular‐weight tau; soluble tau aggregates; synapses; tau aggregation inhibitor; tau oligomers; tau pathology; tau seeding; tauopathy

DOI:  https://doi.org/10.1002/alz.71572