bims-proned 2026-03-15 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–03–15
23 papers selected by
Verena Kohler, Umeå University

Landscape of Protein Post-Translational Modifications in Age-Related Neurodegenerative Disorders: Implications in Protein Aggregation, Altered Cellular Processes, and Therapeutics.
Reversibility and β-sheet formation are decoupled in tau condensate aging.
Dopamine and Rotenone Modulate α-Synuclein Phase Separation and Liquid to Solid Transition.
Ubiquitin-specific peptidase-19 links TDP-43 aggregation to ER stress.
Ferroptosis in Parkinson's disease: a review of molecular mechanisms and emerging therapeutic strategies.
Alzheimer's Aβ catalyzes Tau phase separation and aggregation via early nanocluster solubilization.
Structure of α-Synuclein Bound to Polystyrene Surfaces Probed by Experimental and Theoretical Sum Frequency Generation Spectroscopy.
Lipid Acyl Chain-Driven α-Synuclein Fibril Polymorphisms and Neuronal Pathologies.
Synthetic strategies for small molecule compounds for the treatment of Parkinson's disease: targeting α-synuclein.
In vitro, cellular and in vivo studies of amyloid oligomers structure and toxicity: Challenges and advances.
Betulinic acid exacerbates biomolecular condensation of α-synuclein: possible role in Parkinson's disease.
Structure-function relationship of alpha-synuclein fibrillar polymorphs derived from distinct synucleinopathies.
In silico peptide self-assembly reveals the importance of N-terminal motifs and the inhibition mechanism of the mutation L38M in α-synuclein fibrillation.
Role of Alpha-Synuclein in Frontotemporal Dementia: Narrative Review.
USP14 inhibitor IU1 alleviates amyloid-β mediated toxicity in Alzheimer's disease cell and worm models.
FuzDrop: sequence-based prediction of the propensity of proteins for liquid-liquid phase separation and aggregation.
PROTAC-mediated multi-target protein degradation in Alzheimer's disease: mechanistic insights, therapeutic applications, and translational challenges.
Multiscale Insights into the Ionic-Strength Dependence of α-Synuclein Liquid-Liquid Phase Separation.
A Cu(II) binding site involving Cys18 and His22 displays a buffering effect in copper-induced aggregation of cataract-related human γD crystallin.
Decoding the mechanisms of amyloid-β in synaptic toxicity.
Impaired α-Synuclein aggregate clearance in neuronal cells drive their spread to microglia through tunneling nanotubes.
Toxic mechanisms of amyloid oligomers and therapeutic strategies.
Single-Cell Spatial Proteomics Uncovers Molecular Interconnectivity among Hallmarks of Aging.

ACS Omega. 2026 Mar 03. 11(8): 12865-12885

Landscape of Protein Post-Translational Modifications in Age-Related Neurodegenerative Disorders: Implications in Protein Aggregation, Altered Cellular Processes, and Therapeutics.

Akash Kumar Singh, Tapas K Kundu.

Accumulation of aggregated or nonfunctional proteins during the aging process is a common hallmark of degenerating neurons in various neurodegenerative disorders. Post-translational modifications (PTMs) such as acetylation, methylation, phosphorylation, and ubiquitination, etc. in combination with the protein quality control machinery such as autophagy and proteasome systems are essential for the degradation of these toxic aggregates, to maintain normal protein turnover and function of neurons. Abnormal protein quality control machinery primarily mediated by altered post-translational modifications of various proteins are linked to neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and many others. Accumulating evidence from the past two decades shows that targeting these PTMs with various small molecule activators or inhibitors restores synaptic and cognitive processes associated with these neurodegenerative diseases. Here, in this review, we highlight how these PTMs affect the accumulation and aggregation of nonfunctional proteins in various neurodegenerative diseases. Also, we highlight the current advances in exploring small molecule modulators of modifying enzymes as therapeutic options for these diseases.

DOI: https://doi.org/10.1021/acsomega.5c00905
Proc Natl Acad Sci U S A. 2026 Mar 17. 123(11): e2522993123

Reversibility and β-sheet formation are decoupled in tau condensate aging.

Charlotte M Fischer, Irina A Edu, Tomas Šneideris, Ieva Baronaite, Zenon Toprakcioglu, Leif-Thore Deck, Daoyuan Qian, Rob Scrutton, Lasse Dreyer, Jitao Wen, Daniel E Otzen, Si Wu, Sarah Perrett, Tuomas P J Knowles.

  Neurofibrillary tangles (NFTs) formed from the protein tau disrupt neuronal function in Alzheimer's disease and are strongly associated with cognitive decline. Early events in tau aggregation are increasingly linked to the formation of biomolecular condensates, which lower the energetic barriers to pathological aggregation by acting as intermediates that transition into insoluble assemblies, a mechanism also implicated in other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Despite growing evidence for this pathway, the molecular basis by which reversible condensates evolve into irreversible, pathogenic aggregates has remained unclear. Here, we map the phase behavior, structural transitions, and thermodynamic reversibility of tau during condensate aging. Our results reveal that the two hallmark features of the pathological end state, β-sheet enrichment and irreversible aggregation, emerge at different rates and occupy distinct regions of the phase space, indicating that these properties are mechanistically uncoupled. Notably, we identify tau condensate phases that are β-sheet rich yet thermodynamically reversible, as well as irreversible intermediates that lack β-sheet structure. These findings expand the landscape of tau aggregate species beyond a simple linear progression toward fibrils and highlight a diverse array of intermediates with distinct structural and thermodynamic properties. This decoupling of structure and irreversibility has important implications for understanding tau aggregation mechanisms and may offer targets for therapeutic intervention.

Keywords:  biophysics; intrinsically disordered proteins; liquid–liquid phase separation; microfluidics; protein aggregation

DOI:  https://doi.org/10.1073/pnas.2522993123
Small. 2026 Mar 12. e14922

Dopamine and Rotenone Modulate α-Synuclein Phase Separation and Liquid to Solid Transition.

Riya Bera, Shouvik Manna, Ranjit Shaw, Arpita Bhattacharyya, Samir K Maji.

  Liquid-liquid phase separation (LLPS) of α-Synuclein (α-Syn) is recognized as an early biophysical event driving pathological aggregation in Parkinson's disease (PD). Although 10%-15% of PD cases are due to familial mutations, the remaining cases are sporadic, often linked to various factors, like pesticides and metals. For example, rotenone and dopamine are known to be involved in PD pathology and are suggested to cause changes in α-Syn protein homeostasis, although the mechanism by which they influence α-Syn and cellular toxicity is largely unknown. In this work, we demonstrate that both dopamine and rotenone promote the LLPS of α-Syn. Although rotenone promotes the liquid-to-solid transition almost instantaneously, dopamine, however, maintains a liquid state for a long time and rather delays the solidification process, unlike α-Syn alone. Similarly, exposure to both toxicants resulted in faster LLPS in SH-SY5Y cells. Interestingly, irrespective of their impact on material properties, rotenone promotes the faster formation of oligomers and amyloid fibrils, while dopamine exhibits oligomer formation and delayed fibrillation, both of which result in higher cytotoxicity. Our results provide new insight into the molecular processes underlying PD by indicating that endogenous dopamine stress and environmental toxicants converge on phase-separation dynamics as a common mechanism of α-Syn pathology.

Keywords:  Parkinson's disease; alpha‐Synuclein; dopamine; phase separation; rotenone

DOI:  https://doi.org/10.1002/smll.202514922
Proc Natl Acad Sci U S A. 2026 Mar 17. 123(11): e2514355123

Ubiquitin-specific peptidase-19 links TDP-43 aggregation to ER stress.

Yan Yan, Xinming Wang, Hanna Jeon, Teresa R Kee, Khoi D Tran, Hyunkyoung Lee, Xingyu Zhao, Tian Liu, Simon S Wing, Jung-A A Woo, David E Kang.

  Aggregation and deposition of TAR DNA-binding protein 43 (TDP-43) is a salient pathological signature of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration-TDP (FTLD-TDP). TDP-43 proteostasis and aggregation are controlled by several posttranslational modifications, including ubiquitination. While multiple E3 ubiquitin ligases are known to facilitate TDP-43 clearance, little is known about the role of deubiquitinases (DUBs) in controlling TDP-43 proteostasis. Through an unbiased discovery screen of DUBs, here we identify and demonstrate using in vitro and in vivo models, as well as human brain tissue, that ubiquitin-specific peptidase-19 (USP19) acts as a TDP-43-directed DUB that removes K48- and K63-linked ubiquitin conjugates from TDP-43 and preferentially promotes cytoplasmic aggregation of TDP-43 C-terminal fragments (TDP-CTFs) through its catalytic activity. Specifically, the endoplasmic reticulum (ER)-anchored USP19 isoform (USP19-ER) exhibits superior activity in deubiquitinating TDP-CTFs, enhancing its phase separation and aggregation, compared to its cytosolic isoform (USP19-Cyto). Furthermore, as TDP-CTFs are generated at the ER, USP19 acts to couple the aggregation of TDP-CTFs to ER stress (ATF6, ATF4, IRE1, & CHOP). In humans, USP19 protein levels increase in FTLD-TDP brains, which extensively colocalize with cytoplasmic phospho-TDP-43 (pTDP-43) pathology. Importantly, we demonstrate in vivo that genetic reduction of usp19 mitigates pTDP-43 pathology, astrogliosis, and ER stress while reversing long-term potentiation (LTP) and motor deficits in a mouse model of TDP-43 pathogenesis (TAR4 mice). These findings establish a critical role of USP19 at the nexus of TDP-43 proteostasis and ER stress, implicating its pathogenic role in FTLD-TDP and ALS.

Keywords:  ALS; ER stress; FTD; TDP-43; USP19

DOI:  https://doi.org/10.1073/pnas.2514355123
Front Neurosci. 2026 ;20 1780573

Ferroptosis in Parkinson's disease: a review of molecular mechanisms and emerging therapeutic strategies.

Lingling Wang, Yue Zhang, Lei Guo.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons in the substantia nigra and the presence of Lewy bodies containing aggregated α-synuclein (α-syn). While these pathological hallmarks are well-established, the mechanisms underlying neuronal death remain incompletely understood. Emerging evidence highlights ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, as a critical pathway in PD pathogenesis. This review synthesizes recent advances elucidating the synergistic interplay between α-syn aggregation and ferroptosis. We detail how α-syn aggregation not only directly induces ferroptosis but also disrupts iron homeostasis, while iron accumulation in turn accelerates α-syn fibrillation and oxidative stress, forming a vicious cycle that propagates neurodegeneration. Furthermore, we explore the amplifying role of glial cells-microglia and astrocytes-in this process through the promotion of neuroinflammation, oxidative damage, and dysregulation of iron metabolism. Finally, we discuss promising therapeutic strategies targeting this α-syn-ferroptosis axis, including α-syn aggregation inhibitors, iron chelators, and glia-modulating agents, highlighting their potential as disease-modifying interventions. Together, these insights underscore ferroptosis as a central mechanism in PD and offer new avenues for developing targeted therapies.

Keywords:  Parkinson’s disease (PD); ferroptosis; iron metabolism; neurodegeneration; therapeutic targets

DOI:  https://doi.org/10.3389/fnins.2026.1780573
Nat Commun. 2026 Mar 10.

Alzheimer's Aβ catalyzes Tau phase separation and aggregation via early nanocluster solubilization.

Xun Sun, Yiming Tang, Xue Wang, Guadalupe Pereira Curia, Rebecca Sternke-Hoffmann, Cecilia Mörman, Juan Atilio Gerez, Roland Riek, Guanghong Wei, Jinghui Luo.

Extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated Tau are the two main pathological hallmarks of Alzheimer's disease (AD). Although the co-occurrence and synergistic effects of Aβ and Tau are well established, the mechanisms underlying their interplay in a biomolecular condensate environment remain unclear. Here we show that Aβ40 does not undergo liquid-liquid phase separation (LLPS) but significantly enhances Tau phase separation and is recruited into Tau condensates. This recruitment alters condensate physicochemical properties, accelerates liquid-to-solid maturation, promotes Tau amyloid fibril formation, and increases Tau-mediated cytotoxicity. Notably, prior to condensate formation, Aβ40 transiently solubilizes Tau nanoclusters into smaller species. Simulations further indicate that early interactions are non-specific and mediated by Tau repeat domains, ultimately promoting pathogenic aggregation. These findings support a model wherein Aβ act as a catalyst for Tau condensation and fibrillation towards pathological aggregates by solubilizing Tau nanoclusters during early phase interactions.

DOI: https://doi.org/10.1038/s41467-026-70083-1
Langmuir. 2026 Mar 12.

Structure of α-Synuclein Bound to Polystyrene Surfaces Probed by Experimental and Theoretical Sum Frequency Generation Spectroscopy.

Akriti Mishra, Judith Zubia-Aranburu, Lorena Zuzic, Khezar Saeed, Janni Nielsen, Birgit Schio̷tt, Mingdong Dong, Daniel E Otzen, Tobias Weidner.

Hydrophobic interfaces are ubiquitous, and interactions of proteins with such surfaces remain an area of significant interest. α-Synuclein (α-Syn), a protein abundant in cerebrospinal fluid, is implicated in nearly 50 neurological disorders. The misfolding of α-Syn into amyloid aggregates is a critical step in the progression of several neurodegenerative diseases. Hydrophobic interfaces have been shown to catalyze this process. To better understand the mechanism of aggregation and ultimately aid in the development of therapeutic strategies, it is essential to probe the interfacial structures of α-Syn that may drive amyloid formation. Here, we present a detailed investigation of the interfacial structure of α-Syn on a polystyrene (PS) film, a widely used material in consumer products and laboratory settings. Elucidating the structural motifs of α-Syn at the PS interface provides insights into how plastic contaminants may induce conformational changes in the protein. Combining experimental vibrational sum frequency generation spectroscopy with theoretical spectral calculations, we identify the interfacial structure of α-Syn at the PS film and compare it with previously reported α-Syn conformation on air-water interfaces. The entire NAC region and majority of the residues in the N terminal are in direct contact with the PS surface, while the C terminal residues protrude away from the interface, staying in the solution. Our studies highlight the critical role of polymeric surfaces in facilitating α-Syn misfolding.

DOI: https://doi.org/10.1021/acs.langmuir.5c05658
ACS Chem Neurosci. 2026 Mar 13.

Lipid Acyl Chain-Driven α-Synuclein Fibril Polymorphisms and Neuronal Pathologies.

Yoongyeong Baek, Anika Alim, Yanheng Dong, Tarek Olabi, Jungwook Paek, Myungwoon Lee.

  Conformational variations in α-syn fibrils are thought to underlie the distinct clinical features of synucleinopathies, including Lewy body dementia (LBD), Parkinson's disease (PD), and multiple system atrophy (MSA), suggesting that distinct fibril structures act as molecular fingerprints linked to disease phenotypes. While the origins of these conformational variations remain unclear, increasing evidence points to membranes as key modulators of fibril conformations. In this study, we investigated how age-related alterations in membrane composition and fluidity influence α-syn fibril formation and cellular outcomes. Using complex membrane mixtures that mimic normal neuronal membranes and their age-related modifications in fatty acid chains, we found that α-syn fibrils grown with these membranes displayed distinct 2D ssNMR spectral patterns compared to lipid-free α-syn fibrils, reflecting differences in the rigid fibril cores. Moreover, fibrils grown with age-related membranes exhibited weaker membrane association than those formed with normal neuronal membranes. These membrane-associated fibrils induce stronger neuronal pathologies than lipid-free fibrils, although the severity differed in terms of intraneuronal aggregation and inflammatory responses. Overall, our findings provide new insights into how age-related changes in membrane composition shape α-syn fibril structure and pathogenicity, strengthening the link between membrane dynamics and amyloid-driven neurodegeneration.

Keywords:  fibril polymorphism; membranes; neuronal pathology; solid-state NMR; synucleinopathies; α-synuclein aggregation

DOI:  https://doi.org/10.1021/acschemneuro.5c00730
Mol Divers. 2026 Mar 12.

Synthetic strategies for small molecule compounds for the treatment of Parkinson's disease: targeting α-synuclein.

Bing Ai, Xin-Yu Zhang, Cai-Yun Hu, Zhen Guo, Cheng-Hua Jin.



Keywords:  Aggregation; Inhibitors; Parkinson’s disease; Structure–activity relationships; α-synuclein

DOI:  https://doi.org/10.1007/s11030-026-11510-9
Protein Sci. 2026 Apr;35(4): e70525

In vitro, cellular and in vivo studies of amyloid oligomers structure and toxicity: Challenges and advances.

Magdalena I Ivanova, Carmelo La Rosa, Ayyalusamy Ramamoorthy.

  Oligomeric assemblies of amyloidogenic proteins, such as Aβ, tau, α-synuclein, amylin, transthyretin, and TDP-43, are increasingly recognized as key drivers of cellular dysfunction across a range of neurodegenerative and systemic disorders. However, their molecular properties remain poorly understood due to their low abundance, structural heterogeneity, and transient nature. This review outlines current methods for studying amyloid oligomers, including biophysical (NMR, cryo-EM, HS-AFM, mass spectrometry), computational (molecular dynamics simulations), and biological (cellular assays, organoids, and animal models) approaches. This review also covers emerging methods for detecting misfolded proteins within complex biological environments and live-cell systems. Furthermore, we discuss recent advances that specifically address the challenges of studying oligomers, which are yielding crucial data on how these pathogenic species impair cellular homeostasis. Given the heterogeneity and transient nature of the oligomers, it is essential to utilize findings across diverse experimental platforms that yield complementary data and apply methods that also ensure reproducibility and mechanistic clarity with the goal of translating these findings into effective therapeutic strategies.

Keywords:  amyloid; biophysical methods; cellular models; disease; oligomers; polymorphism; protein aggregation; protein misfolding; structure

DOI:  https://doi.org/10.1002/pro.70525
Biomater Sci. 2026 Mar 09.

Betulinic acid exacerbates biomolecular condensation of α-synuclein: possible role in Parkinson's disease.

Soumojit Biswas, Karthik P, Nimisha A Mavlankar, Asish Pal, Ipsita Roy.

Aggregation of α-synuclein (α-SYN) into amyloid structures is closely linked to progression of Parkinson's disease (PD). Type 2 diabetes mellitus increases PD risk, sharing common pathological features like amyloid aggregation, insulin dysregulation, inflammation, oxidative stress, and mitochondrial dysfunction. Insulin resistance affects over 60% of PD cases, leading to trials of anti-diabetic drugs for potential PD benefits. The monomeric form of α-SYN tends to aggregate in a process that relies on nucleation, ultimately leading to the formation of insoluble fibrils. Recent research indicates that the smaller, low-molecular-weight aggregates known as "soluble oligomers" may actually be the main culprits behind neurotoxicity, rather than the larger fibrils themselves. Betulinic acid (BA), a natural lupane triterpenoid, has shown anti-diabetic properties in several model systems, making it a promising candidate for investigation in PD. In this work, the role of BA in modulation of aggregation of different pathological variants of α-synuclein, such as wild type, A30P mutant, phosphomimetic S129D variant and C-terminal truncated variant, has been investigated. The results indicate that BA enhances the phase partitioning of all disease-relevant variants of α-SYN. The droplet size of the condensate was the smallest for the A30P variant and the highest for the C-terminal truncated protein and it increased uniformly for all variants in the presence of BA. Increased restriction in rotation of the biomolecular condensate was seen in the presence of this triterpenoid, which matched with enhanced sol-to-gel transition and higher storage and loss moduli of the hydrogel formed. This led to increased protein aggregation and toxicity as evidenced by the decreased survival rates of yeast and mammalian cells expressing α-SYN variant aggregates when treated with BA. Toxicity was likely due to the formation of soluble oligomeric species. Long-term use of BA under any therapy regimen, particularly at high doses, may result in considerable side effects, potentially heightening the risk of developing PD over time. Hence, in further developmental studies of BA in different disease conditions, the long-term side effects of this triterpenoid need to be monitored.

DOI: https://doi.org/10.1039/d5bm01817j
Mol Syst Biol. 2026 Mar 11.

Structure-function relationship of alpha-synuclein fibrillar polymorphs derived from distinct synucleinopathies.

Tetiana Serdiuk, Virginie Redeker, Jimmy Savistchenko, Sandesh Neupane, Walther Haenseler, Yanick Fleischmann, Viviane Reber, Sabrina Keller, Cinzia Tiberi, Ruxandra Bachmann-Gagescu, Matthias Gstaiger, Thomas Braun, Roland Riek, Steve Gentleman, Adriano Aguzzi, Natalie de Souza, Ronald Melki, Paola Picotti.

  The aggregation of the protein alpha-synuclein (αSyn) is a common feature of multiple neurodegenerative diseases collectively called synucleinopathies, for which the pathobiology is not well understood. The different phenotypic characteristics of the synucleinopathies Parkinson's disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) have been proposed to originate from the distinct structures adopted by αSyn in its amyloid forms. Here, using covalent labeling and limited proteolysis coupled to mass spectrometry (LiP-MS) in vitro and in situ within neuronal cells and directly in native patient brain homogenates, we show that pathogenic αSyn from distinct synucleinopathies (PD, DLB and MSA) are structurally different. Further, we found that fibril structural differences are associated with different putative fibril interactomes and neuronal responses. We discovered disease-specific ubiquitination patterns and turnover profiles for pathogenic αSyn species, detected molecular pathways responding specifically to the uptake of different αSyn fibrillar polymorphs, and identified a subset of the involved proteins as putative interactors of αSyn. In particular, components of the ubiquitin-proteasomal System (UPS), including E3 ubiquitin ligases, chaperones, and deubiquitinating proteins, showed disease/polymorph-specific putative interaction patterns, possibly accounting for different resistance of patient-derived αSyn fibrils to degradation. Genetic modulation with CRISPR-based tools showed that members of the UPS degradation pathway (three E3 ligases: UBE3A, TRIM25, HUWE1 and the AAA+ ATPase VCP) reduced αSyn inclusions, in a strain-specific manner. LiP-MS also identified sets of proteins with altered protease susceptibility in postmortem brain homogenates of PD, DLB, and MSA patients. These sets were largely disease-specific and included proteins altered in cells treated with fibrils derived from patients with the matching disease. Our findings provide insight into cellular processes involved in the accumulation and turnover of αSyn pathogenic aggregates in PD, DLB and MSA in a disease/specific manner and constitutes a resource of potential novel drug targets in these synucleinopathies.

Keywords:  Alpha-Synuclein; Amyloid Strains; Limited Proteolysis-Coupled to Mass Spectrometry; Parkinson’s Disease; Structural Proteomics

DOI:  https://doi.org/10.1038/s44320-026-00199-5
Protein Sci. 2026 Apr;35(4): e70530

In silico peptide self-assembly reveals the importance of N-terminal motifs and the inhibition mechanism of the mutation L38M in α-synuclein fibrillation.

Van T T Nguyen, Sabine M Ulamec, David J Brockwell, Sheena E Radford, Carol K Hall.

  Alpha-synuclein (αSyn) is a presynaptic protein associated with several neurodegenerative diseases. While the non-amyloid component (NAC) region of the αSyn sequence (residues 65-90) forms the core of all αSyn fibrils, recent findings suggest that the flanking regions play a key role in initiating or preventing amyloid formation. Two motifs in the N-terminal region, named P1 (αSyn [36-42]) and P2 (αSyn [45-57]), have been shown to be key modulators of fibril formation, with deletion of these regions or single-point mutations in the P1 region inhibiting amyloid formation of full-length αSyn. In this study, we use the coarse-grained molecular dynamics package DMD/PRIME20 to simulate the self-assembly of the P1 and P2 regions, alongside longer segments P3 (αSyn [36-57]) and P3Next (αSyn [27-57]), and single-point mutations: focusing primarily on L38M, L38A, and V40A, and additionally examining Y39A and S42A as secondary variants, all of which have different effects on fibril formation of the full-length protein in vitro. The results show that P1, P2 and P3 have a high propensity to form parallel β-sheets while P3Next tends to form β-hairpins within fibrillar structures. The L38M substitution reduces the formation of both parallel β-sheets and β-hairpins, consistent with the inability of full-length αSyn containing L38M to form amyloid fibrils in vitro at neutral pH and to aggregate in vivo in Caenorhabditis elegans. In contrast, simulations of L38A and V40A show no such effect, consistent with their minimal impact on full-length αSyn fibrillation. The simulation results suggest that the presence of P1/P2 hairpins are required to unleash the amyloid potential of αSyn and offer a structural explanation of how L38M mutation in this region protects the protein from amyloid formation.

Keywords:  DMD/PRIME20 simulations; N‐terminal motifs/segments/fragments; amyloid fibril formation; inhibitory mechanism; mutation inhibitor; parallel β‐sheets; peptide self‐assembly; α‐synuclein; β‐hairpins

DOI:  https://doi.org/10.1002/pro.70530
Cells. 2026 Mar 05. pii: 470. [Epub ahead of print]15(5):

Role of Alpha-Synuclein in Frontotemporal Dementia: Narrative Review.

Anastasia Bougea.

   BACKGROUND: Frontotemporal dementia (FTD) is traditionally classified based on the accumulation of either tau or TDP-43 proteins; however, the presence of alpha-synuclein (α-Syn) in these patients is increasingly recognized as a critical factor driving disease progression.
METHODS: A comprehensive narrative review of recent clinical, neuropathological, and biochemical studies was conducted, focusing on cases of FTLD-synuclein and the occurrence of alpha-syn as a co-pathology in more common FTD variants.
RESULTS: Current evidence indicates that α-syn often co-aggregates with tau and TDP-43 via "cross-seeding" mechanisms, significantly accelerating neuronal loss and contributing to clinical heterogeneity. Although FTLD-synuclein is a rare, distinct subtype that mimics atypical multiple system atrophy, secondary α-syn pathology is common and strongly correlates with rapid cognitive decline. Furthermore, existing diagnostic biomarkers typically fail to detect this pathological overlap, which may explain the limited efficacy in protein-specific clinical trials.
CONCLUSIONS: α-Syn is a major, yet under-recognized, catalyst of neurodegeneration within the FTD spectrum. The findings emphasize the need for future therapeutic and diagnostic strategies to adopt multi-target approaches, addressing the synergistic toxicity of multiple protein aggregates rather than isolating single protein in isolation.

Keywords:  FTLD-synuclein; TDP-43; alpha-synuclein; biomarkers; co-pathology; cross-seeding; frontotemporal dementia; neurodegeneration; proteinopathy; tau

DOI:  https://doi.org/10.3390/cells15050470
J Alzheimers Dis. 2026 Mar 13. 13872877261422775

USP14 inhibitor IU1 alleviates amyloid-β mediated toxicity in Alzheimer's disease cell and worm models.

Ajish Ariyath, Eugene Hone, W M A D Binosha Fernando, Steve Pedrini, Ralph Martins, Prashant Bharadwaj.

  BackgroundProteostasis dysfunction plays a central role in Alzheimer's disease (AD), where aberrant accumulation of amyloid precursor protein (APP)-derived peptides, including APP-C99 and amyloid-β (Aβ), contributes to neurotoxicity. Previous work with an APP-C99 neuronal cell model revealed impaired proteasome activity, lysosomal dysfunction, and increased autophagic markers LC3 and p62.ObjectiveTo identify small molecule modulators of proteostasis that reduce Aβ-mediated toxicity and to evaluate their mechanism of action in both cellular and C. elegans models of AD.MethodsWe screened a library of small molecule proteostasis modulators in the APP-C99 cell model to identify compounds that reduce Aβ-mediated cell death. Hits were further analyzed for their effects on APP-C99/Aβ clearance, autophagy, and proteasomal function. Neuroprotective effects were validated in an AD C. elegans model.ResultsThe USP14 deubiquitinase inhibitor IU1 increased cell survival by 40%, reduced APP-C99 and Aβ accumulation, restored proteasomal activity, LC3 and p62 levels to control. IU1 also decreased neuronal loss and improved survival and behavior in AD worms. Notably, autophagy activators, including mTOR inhibitors rapamycin, everolimus, and temsirolimus, worsened Aβ toxicity. Conversely, autophagy inhibitors such as Bafilomycin A and chloroquine reduced APP-C99/Aβ accumulation, enhanced proteasomal activity, decreased cell death, and improved neurodegeneration and behavior in the worm model.ConclusionsThis study reveals that, under Aβ-mediated proteostasis dysfunction, autophagy activation exacerbates toxicity, whereas proteasome activation via allosteric inhibition of USP14 using IU1 was neuroprotective. These findings provide evidence to suggest that targeting proteasome stimulation via pharmacological inhibition of USP14 offers a promising therapeutic strategy for AD.

Keywords:  Alzheimer’s disease; C. elegans; amyloid precursor protein; amyloid-β protein; autophagy; ubiquitin-proteasome systems

DOI:  https://doi.org/10.1177/13872877261422775
Nat Protoc. 2026 Mar 11.

FuzDrop: sequence-based prediction of the propensity of proteins for liquid-liquid phase separation and aggregation.

Michele Vendruscolo, Monika Fuxreiter.

Proteins exhibit complex phase behavior as they convert between the native state, the liquid condensate (or droplet) state and the solid condensate (or amyloid) state. To facilitate the study of these processes, we describe the FuzDrop method of predicting the condensation propensity of proteins to undergo liquid-liquid phase separation and to subsequently form amyloid aggregates. The method is based on the principle that liquid condensations reflect a balance between enthalpic and entropic contributions; FuzPred is an algorithm that provides sequence-based estimates for these contributions in stoichiometric complexes ( https://fuzpred.bio.unipd.it/predictor ). FuzDrop extends this algorithm to protein condensates, and enables prediction of the propensity for amyloid formation within liquid condensates, known as the condensation pathway to protein aggregation ( https://fuzdrop.bio.unipd.it/predictor ). This prediction is based on the principle that the sequence regions that promote aggregation within liquid condensates have a multiplicity of binding modes, because they have a strong propensity for both entropic-driven interactions to stabilize the droplet state and enthalpic-driven interactions to stabilize the amyloid state. The time required for FuzDrop predictions on the web server scales linearly with protein length and is typically ~30 s for a protein of 500 residues. By enabling predictions of protein phase behavior, FuzDrop may facilitate experimental studies directed at the development of therapies for protein condensation diseases.

DOI: https://doi.org/10.1038/s41596-025-01267-0
RSC Med Chem. 2026 Feb 20.

PROTAC-mediated multi-target protein degradation in Alzheimer's disease: mechanistic insights, therapeutic applications, and translational challenges.

Bin Wang, Yunan Li, Tingting Yao, Xinai Shen, Huan Li, Wei Jiang, Xinuo Li, Zheying Zhu.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by multiple interacting pathological mechanisms. Among these, the core driving factor is the accumulation of abnormally folded, neurotoxic proteins. Current therapeutic options, particularly immunotherapies, remain limited due to their reliance on immune-mediated clearance, the need for high-dose administration, and their inability to access intracellular targets, making them less patient-friendly and therapeutically efficient. This is precisely where proteolysis-targeting chimera (PROTAC) technology offers a transformative advantage. By harnessing the ubiquitin-proteasome system (UPS), PROTACs can selectively recruit degradation machinery to target proteins, thereby facilitating their ubiquitination and subsequent clearance. This mechanism allows PROTACs to efficiently eliminate pathogenic proteins while overcoming several inherent limitations of both traditional occupancy-based inhibitors and antibody-based therapies. In this review, we compare currently available AD therapies to highlight the advantages and mechanistic rationale underlying the promise of PROTAC technology in this field. We further discuss the molecular principles of PROTAC-mediated protein degradation and its emerging applications in tackling protein aggregation pathologies, focusing on both established and novel therapeutic targets. By drawing insights from existing PROTAC studies, we aim to inform future design strategies that reduce off-target effects, accelerate candidate optimization, and ultimately contribute to the development of a new generation of AD therapeutics.

DOI: https://doi.org/10.1039/d5md00963d
Macromol Rapid Commun. 2026 Mar 10. e00966

Multiscale Insights into the Ionic-Strength Dependence of α-Synuclein Liquid-Liquid Phase Separation.

Chen Chen, Zeng-Shuai Yan, Yu-Qiang Ma, Hong-Ming Ding.

  Liquid-liquid phase separation (LLPS) of α-synuclein (α-syn) is an early step toward pathogenic aggregation, yet how sequence architecture and ionic strength jointly regulate this process remains unresolved. Here, we combine all-atom and coarse-grained molecular dynamics simulations to connect single-chain conformational ensembles with multichain condensate formation of α-syn. The highly disordered nature of the α-syn monomer is consistently captured by both all-atom simulations and coarse-grained simulations. We find that the LLPS behavior of full-length α-syn is strongly dependent on ionic strength. Low to intermediate NaCl concentrations favor the formation of liquid-like condensates characterized by high internal mobility and continuous exchange with the dilute phase. As ionic strength increases, electrostatic screening weakens intermolecular interactions, and LLPS is progressively attenuated and ultimately suppressed. We next examined the phase-separation propensities of the N-terminal, NAC, and C-terminal fragments. Strikingly, robust phase separation is observed only for the N-terminal region due to electrostatic interactions, whereas the NAC and C-terminal fragments exhibited only weak, short-lived clustering without forming persistent condensates. Together, our multiscale results establish a mechanistic link between salt-mediated electrostatic screening, region-encoded conformational landscapes, and α-syn condensate formation, providing molecular insight into how solution conditions may tune early events along the pathway to aggregation.

Keywords:  all‐atom molecular dynamics (MD) simulation; coarse‐grained MD simulation; liquid–liquid phase separation; salt concentration; α‐synuclein

DOI:  https://doi.org/10.1002/marc.202500966
J Inorg Biochem. 2026 Mar 02. pii: S0162-0134(26)00078-4. [Epub ahead of print]280 113289

A Cu(II) binding site involving Cys18 and His22 displays a buffering effect in copper-induced aggregation of cataract-related human γD crystallin.

Eusebio Uc-Santos, Liliana Quintanar.

  Cataracts are the main cause of blindness in the world, and they are caused by aggregation of lens crystallin proteins. Metal ions have emerged as a potential factor in the development of cataract disease, as copper and zinc ions induce the non-amyloid aggregation of lens crystallins in vitro. Copper-induced aggregation of human γD crystallin (HγD) involves disulfide and metal bridging, partial unfolding of the protein and copper reductase activity. In this study, the effect of the double mutation C18S/H22Q in the copper-induced aggregation of HγD was evaluated by turbidity assays, electrophoresis and transmission electron microscopy, finding that the mutation renders HγD more susceptible to copper-induced aggregation. Electron paramagnetic resonance (EPR) and X-ray absorption spectroscopy (XAS) show that the C18S/H22Q mutation does not abolish copper reductase activity of HγD, and that Cys18 and His22 constitute a Cu(II) binding site with a 2N1S1O coordination sphere. This site displays a metal-buffering effect, and in its absence, copper-induced aggregation of HγD crystallin is exacerbated by a metal-bridging mechanism involving other Cu(II) binding sites. This study reveals the presence of a copper-buffering site in HγD crystallin that protects it from aggregation; this would be of functional relevance to prevent development of cataracts upon loss of cellular redox balance and metal homeostasis in the context of an aging lens.

Keywords:  Cataracts; Copper ions; Crystallins; Electronic paramagnetic resonance; Protein aggregation; X-ray absorption spectroscopy

DOI:  https://doi.org/10.1016/j.jinorgbio.2026.113289
J Alzheimers Dis. 2026 Mar 13. 13872877261424292

Decoding the mechanisms of amyloid-β in synaptic toxicity.

Piotr Toruński, Giusy Pizzirusso, Bengt Winblad, Luis Enrique Arroyo-García.

  Amyloid-β (Aβ) aggregation is considered a central hallmark in the pathophysiology of Alzheimer's disease (AD). Aβ protein aggregates disrupt synaptic architecture, calcium homeostasis, and mitochondrial function, leading to excitotoxicity and synaptic plasticity deficits. Animal models and human studies reveal that Aβ-induced alterations in synaptic activity and neuronal circuit function appear before irreversible damage and the onset of cognitive impairment. This review examines the multifaceted effects of Aβ on synaptic and neuronal circuits across its distinct aggregation states, including monomeric, oligomeric, protofibrillar, and fibrillar forms. Its novelty lies in providing a comprehensive map of Aβ-induced mechanisms that disrupt neuronal electrical function, based on electrophysiological evidence from neuronal cultures, animal models, and patient studies, with a particular focus on preclinical stages of cognitive decline. We suggest that the Aβ-induced synaptic toxicity could serve, first, as a complementary biomarker of brain deterioration and second, as a readout of current AD therapies. This could potentially lead to better outcomes in AD treatments.

Keywords:  Alzheimer's disease; amyloid-β; excitotoxicity; neuronal function; oscillatory activity; synaptic plasticity

DOI:  https://doi.org/10.1177/13872877261424292
Nat Commun. 2026 Mar 12.

Impaired α-Synuclein aggregate clearance in neuronal cells drive their spread to microglia through tunneling nanotubes.

Ranabir Chakraborty, Francesca Palese, Philippa Samella, Veronica Testa, Jara Montero-Muñoz, Sylvie Syan, Takashi Nonaka, Masato Hasegawa, Antonella Consiglio, Chiara Zurzolo.

Tunneling nanotubes (TNTs) play a crucial role in intercellular communication, enabling transfer of molecular cargoes over long distances between connected cells. Previous studies have demonstrated efficient, directional transfer of α-Synuclein (α-Syn) aggregates from neurons to microglia, with endosomal trafficking and lysosomal processing identified as the primary events following α-Syn internalization. Using human neuronal and microglial cell lines, we show that microglia exhibit higher lysosomal turnover, particularly through lysophagy, whereas neuronal lysosomes display compromised degradative capacity and impaired autophagic flux upon α-Syn exposure, resulting in compromised aggregate clearance. Such a response to α-Syn aggregates is also conserved in human iPSC-derived neurons and microglia. Moreover, perturbing aggregate clearance via autophagy inhibition enhances TNT-mediated transfer of α-Syn from neuronal cells to microglia. Microglia co-cultured with α-Syn-containing neurons upregulate autophagy flux, enabling efficient degradation of the transferred aggregates. These results highlight dysfunctional autophagy in neurons as a key driver outsourcing α-Syn aggregates to microglia.

DOI: https://doi.org/10.1038/s41467-026-69930-y
Protein Sci. 2026 Apr;35(4): e70519

Toxic mechanisms of amyloid oligomers and therapeutic strategies.

Magdalena I Ivanova, Carmelo La Rosa, Ayyalusamy Ramamoorthy.

  Amyloid oligomers are increasingly recognized as the major toxic contributors across protein-misfolding disorders. In this review, we cover mechanistic evidence showing how these transient and structurally heterogeneous oligomers disrupt cellular homeostasis by: (i) permeabilizing lipid membranes and forming ion-conducting pores; (ii) triggering endoplasmic reticulum (ER) stress and unfolded protein response (UPR), thereby compromising proteostasis via dysfunction of the ubiquitin-proteasome system (UPS) and autophagy; (iii) impairing mitochondrial function and disrupting redox balance; (iv) interfering with endosomal-lysosomal as well as axonal and synaptic trafficking; and (v) activating stress-kinase signaling and apoptotic pathways. In relation to therapeutic intervention, we review secretase-targeting strategies, conformation-selective antibodies, and their mixed clinical outcomes. An in-depth understanding of the toxic action of pathogenic oligomeric species will be critical for translating these mechanistic insights into effective therapies that comprehensively target oligomer toxicity.

Keywords:  amyloid disease; neurodegeneration; oligomers; prions; protein misfolding; therapies; toxicity mechanisms

DOI:  https://doi.org/10.1002/pro.70519
bioRxiv. 2026 Feb 28. pii: 2026.02.26.708335. [Epub ahead of print]

Single-Cell Spatial Proteomics Uncovers Molecular Interconnectivity among Hallmarks of Aging.

Seungmin Yoo, Christopher Young, Liying Li, Lingraj Vannur, Junming Zhuang, Fan Zheng, Meiying Wu, Julie K Andersen, Chuankai Zhou.

Aging is accompanied by conserved hallmarks including genomic instability, epigenetic alterations, loss of proteostasis, and mitochondrial dysfunction, but how these processes emerge and become mechanistically linked remains unclear. Here we leverage a proteome-wide, single-cell, subcellular atlas of protein expression, localization, and aggregation across yeast replicative aging to map hallmark-linked remodeling in its spatial context. We identify hundreds of previously unappreciated molecular changes that underlie major hallmarks of aging and show that hallmark phenotypes frequently manifest as compartment-specific erosion of spatial confinement, relocalization, and aggregation. 91.6% human orthologs of these hallmark-linked yeast proteins also change during human aging. Integrating these spatial phenotypes reveals many molecular connections linking different hallmarks. Temporal analysis suggests that disorganization of nucleolar ribosome biogenesis, proteostasis decline, and mitochondrial dysfunction precede other hallmarks. Together, our findings substantially deepen the molecular underpinnings of aging hallmarks and provide a framework for linking them into a hierarchical sequence of cellular failures.

DOI: https://doi.org/10.64898/2026.02.26.708335