bims-proned 2026-02-15 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–02–15
sixteen papers selected by
Verena Kohler, Umeå University

Interactions Between Nutraceuticals and α-Synuclein Conformational States: Molecular Mechanisms and Neuroprotective Implications in Parkinson's Disease.
Pharmacological inhibition of O-GlcNAcase reduces pS129-α-synuclein positive aggregates in the substantia nigra of mThy1-hSNCA mice.
Function within Disorder: Small heat shock proteins use different functional regions to chaperone tau aggregation.
From Evasion to Collapse: The Kinetic Cascade of TDP-43 and the Failure of Proteostasis.
Golgi fragmentation driven by the USP11-ITCH axis triggers autolysosomal failure in neurodegeneration.
Modulation of Host Proteostasis by Prevotella corporis via Induction of the Heat Shock Response.
Amyloid β-Cholesterol Interplay: Removal of Cholesterol From the Membranes to Catalyze Aggregation and Amyloid Pathology.
Nrf2-Activating Natural Compounds in Neurodegenerative Diseases: Targeting Oxidative Stress and Protein Aggregation.
Gangliosides GM3 And GD3 Modulate Insulin Aggregation Pathways and Reduce Cytotoxicity Through Structural Remodeling.
Scaffold-client behavior and structural organization in multicomponent protein condensates as revealed by studying tau/TDP-43 droplets.
Pathological TDP-43 filaments accumulate at synapses and cause synaptic dysfunction.
Dynamic conformational ensembles of soluble Tau encode neuronal toxicity prior to aggregation.
A HaloTag-4R-Tau Pulse-Chase Sensor Reveals Neddylation Inhibition Promotes Degradation of Tau in iNeurons.
Big Tau: Structure, Evolutionary Divergence, and Emerging Roles in Cytoskeletal Dynamics and Tauopathies.
Multilayer modulation of the proteasome: new strategies for neuroprotection.
TDP-43 Mediates Autophagic Degradation of Yki by Stabilizing Ref(2)P in Drosophila.

Int J Mol Sci. 2026 Jan 28. pii: 1324. [Epub ahead of print]27(3):

Interactions Between Nutraceuticals and α-Synuclein Conformational States: Molecular Mechanisms and Neuroprotective Implications in Parkinson's Disease.

Bruna Amenta, Rosalba Minervini, Maria Laura Matrella, Tiziana Cocco.

  Synucleinopathies, including Parkinson's disease (PD), are neurodegenerative disorders characterized by aberrant aggregation of α-synuclein (α-syn), a presynaptic protein with an intrinsic disorder nature. The transition of soluble monomers into oligomeric and fibrillar species represents a key molecular event driving neuronal dysfunction and neurodegeneration. Emerging evidence suggests that nutraceuticals, bioactive compounds derived from dietary sources, can modulate α-syn aggregation at multiple conformational stages. Polyphenols, alkaloids, ginsenosides, and food-derived peptides interfere with α-syn structure and assembly, suppressing the formation of toxic oligomer species and promoting the clearance of misfolded assemblies. Despite this potential, clinical translational of nutraceuticals is currently limited by poor systemic bioavailability and restricted central nervous system penetration due to blood-brain barrier constraints, which have largely confined research to preclinical studies. In this context, this review summarizes current knowledge of nutraceutical interventions targeting the conformational landscape of α-syn and highlighting both direct and indirect molecular mechanisms with involved in aggregation-prone species. Furthermore, we critically examine key challenges related to bioavailability and clinical translation, focusing on advanced delivery systems and precision-based approaches to enhance neuroprotective efficacy and support the potential of nutraceuticals as novel or adjunctive therapeutic strategies for PD.

Keywords:  conformational landscape; neurodegeneration; nutraceuticals; protein misfolding; α-synuclein

DOI:  https://doi.org/10.3390/ijms27031324
J Parkinsons Dis. 2026 Feb 10. 1877718X251410291

Pharmacological inhibition of O-GlcNAcase reduces pS129-α-synuclein positive aggregates in the substantia nigra of mThy1-hSNCA mice.

Jefferey Yue, Bryan Jones, Kim H Tran, Matthew Deen, Viktor Holicek, Wai Hang Cheng, Mateusz Michalik, Sarah Power, Cheryl L Wellington, Neil V Watson, David J Vocadlo.

  BackgroundThe aggregation and spread of α-synuclein within brain are associated with the loss of dopaminergic neurons and the formation of Lewy bodies as seen in Parkinson's disease. Blocking the initiation of α-synuclein aggregation, or the spread of such aggregates, may offer disease-modifying approaches to slow disease progression. Previous studies have demonstrated that modification of aggregation prone proteins, including α-synuclein, with O-linked β-N-acetylglucosamine (O-GlcNAc) reduces their aggregation. Small molecule inhibitors of the enzyme O-GlcNAcase (OGA), which removes O-GlcNAc from proteins, confers neuroprotective benefits in various preclinical disease models of Alzheimer's and Parkinson's diseases.ObjectiveThis study investigates the effects of long-term pharmacological enhancement of O-GlcNAcylation in a transgenic mouse model of Parkinson's disease overexpressing human α-synuclein.MethodsThiamet-G was orally administered to mThy1-hSNCA and wild-type (WT) mice for ten months. Behavioral assessments were conducted to examine changes in locomotion and cognition. Histological analyses were performed to analyze α-synuclein aggregates and dopaminergic neurons in brain sections. Immunoblot and ELISA analyses were performed to analyze O-GlcNAc and soluble α-synuclein using brain lysates, respectively.ResultsThiamet-G increased the level of O-GlcNAc in the brain of both mThy1-hSNCA and WT mice. The levels of total α-synuclein in the brain were unaltered. However, Thiamet-G strongly attenuated the deposition of pS129-immunoreactive α-synuclein aggregates within the substantia nigra, prior to observable neurodegeneration. Thiamet-G also protected against locomotor decline.ConclusionsThese results support OGA inhibition as a therapeutic approach to block the pathological formation of toxic α-synuclein as a disease-modifying treatment against Parkinson's disease.

Keywords:  Lewy bodies; O-GlcNAc; Parkinson's disease; mouse model; α-Synuclein

DOI:  https://doi.org/10.1177/1877718X251410291
bioRxiv. 2026 Jan 29. pii: 2026.01.28.702414. [Epub ahead of print]

Function within Disorder: Small heat shock proteins use different functional regions to chaperone tau aggregation.

Mia Cervantes, Maria K Janowska, Lisa M Tuttle, Abhinav Nath, Rachel E Klevit.

In numerous neurodegenerative diseases known collectively as tauopathies, the microtubule-associated protein tau forms fibrillar aggregates that are hallmarks of disease pathology. Tauopathies represent a substantial fraction of diseases associated with protein misfolding. Cellular chaperones known as small heat shock proteins (sHSPs) play a critical role in maintaining protein homeostasis by delaying the onset of protein aggregation. Two sHSPs, HSPB1 (Hsp27) and HSPB5 ( α B-crystallin), are constitutively expressed in brain and neurons. Here, we show that HSPB1 and HSPB5 delay tau aggregation in vitro through distinct mechanisms dictated by their disordered N-terminal regions (NTRs). HSPB1 inhibits tau aggregation under normal cellular conditions, whereas HSPB5 displays activity towards tau when activated by stress conditions such as pH acidosis. Using chimeric HSPB1/HSPB5 constructs in which small NTR subregions are swapped, we identify functional regions within the NTRs that modulate chaperone function for tau. The functional regions contain known sites of phosphorylation, suggesting that they are also control points that respond to cellular stress conditions. Our findings support an emerging model in which specific functional motifs within disordered regions of sHSPs govern activity and client engagement under normal and stress conditions.
Broader Audience: In many neurodegenerative diseases, the microtubule-associated protein tau forms fibrillar aggregates in the brain. Small heat shock proteins (sHSP) help prevent such aggregation, but their mechanisms of action remain enigmatic. We show HSPB1 and HSBP5, two sHSPs that are abundant and co-localize with tau, delay the onset of tau aggregation through distinct mechanisms. Each relies on specific small regions within their disordered N- terminal domains whose accessibility can be regulated by stress conditions and post- translational modifications.

DOI: https://doi.org/10.64898/2026.01.28.702414
Int J Mol Sci. 2026 Jan 23. pii: 1136. [Epub ahead of print]27(3):

From Evasion to Collapse: The Kinetic Cascade of TDP-43 and the Failure of Proteostasis.

Angelo Jamerlan, John Hulme.

  Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases that, despite the availability of symptomatic and modestly beneficial treatments, still lack therapies capable of halting disease progression. A histopathological hallmark of both diseases is the cytoplasmic deposition of TDP-43 in neurons, which is attributed to both intrinsic (e.g., mutations, aberrant cleavage) and extrinsic factors (e.g., prolonged oxidative stress, impaired clearance pathways). Mutations and certain PTMs (e.g., cysteine oxidation) destabilize RNA binding, promoting monomer misfolding and increasing its half-life. Disruptions to core ubiquitin-proteasome system (UPS) subunits impede efficient processing, contributing to the clearance failure of misfolded TDP-43 monomers. The accumulation of monomers drives phase separation within stress granules, creating nucleation hotspots that eventually bypass the thermodynamic barrier, resulting in exponential growth. This rapid growth then culminates in the failure of the autophagy-lysosome pathway (ALP) to contain the aggregation, resulting in a self-sustaining feed-forward loop. Here, we organize these factors into a conceptual kinetic cascade that links TDP-43 misfolding, phase separation, and clearance failure. Therapeutic strategies must therefore move beyond simple clearance and focus on targeting these kinetic inflection points (e.g., oligomer seeding, PTM modulation).

Keywords:  TDP-43 proteinopathy; amyotrophic lateral sclerosis (ALS); autophagy-lysosome pathway (ALP); frontotemporal dementia (FTD); neurodegeneration; phase separation; post-translational modifications (PTMs); proteostasis collapse; ubiquitin-proteasome system (UPS)

DOI:  https://doi.org/10.3390/ijms27031136
Autophagy. 2026 Feb 10. 1-2

Golgi fragmentation driven by the USP11-ITCH axis triggers autolysosomal failure in neurodegeneration.

Qiwang Xiang, Yang Liu, Jiou Wang.

  Golgi fragmentation is a prominent early hallmark of neurodegenerative diseases such as Alzheimer disease (AD) and amyotrophic lateral sclerosis (ALS), yet the shared molecular mechanisms underlying this phenomenon remain poorly understood. Here we identify the E3 ubiquitin ligase ITCH as a central regulator of Golgi integrity and proteostasis. Elevated ITCH disrupts both cis- and trans-Golgi networks, dislocates lysosomal hydrolase sorting factors, and impairs maturation of hydrolases. The ensuing lysosomal dysfunction leads to autophagosome accumulation and defective clearance of accumulated cytoplasmic toxic proteins like TARDBP/TDP-43. Genetic and pharmacological inhibition of ITCH restores autolysosomal degradation and protects neurons in both mammalian and Drosophila models. Aberrant buildup of the deubiquitinase USP11 drives ITCH accumulation, intensifying neuronal proteotoxic stress in individuals with AD and ALS. These findings reveal a mechanistic pathway connecting Golgi disorganization, autolysosomal impairment, and proteotoxic stress in neurodegeneration.

Keywords:  Autophagy; Golgi fragmentation; ITCH; USP11; lysosome; neurodegenerative diseases

DOI:  https://doi.org/10.1080/15548627.2026.2629295
Cell Stress Chaperones. 2026 Feb 10. pii: S1355-8145(26)00006-4. [Epub ahead of print] 100150

Modulation of Host Proteostasis by Prevotella corporis via Induction of the Heat Shock Response.

Matthew F Tibi, Yoan M Argote, Alyssa C Walker, Swapnil Pandey, Cristian Puente, Garrett L Ellward, Anan Safwat, Diego E Rincon-Limas, Daniel M Czyż.

  Neurodegenerative protein conformational diseases (PCDs) are progressive, currently incurable disorders driven by toxic protein aggregation that leads to neuronal death. Emerging evidence supports a microbial role in PCDs, including the most prevalent: Alzheimer's and Parkinson's disease. While metagenomic studies consistently associate gut dysbiosis with these disorders, the mechanisms by which microbes influence host proteostasis remain poorly understood. In particular, considerable attention has been given to proteotoxic bacteria, but the mechanisms by which commensal microbes confer proteoprotection remain largely unexplored. We have previously employed Caenorhabditis elegans models to characterize the role of over 220 bacterial isolates on host proteostasis. Strikingly, members of the Prevotella genus exhibited proteoprotective effects. Most notably, transient exposure to P. corporis uniquely induced Hsp70, a critical molecular chaperone that maintains proteostasis, and significantly reduced aggregation of polyglutamine (polyQ), Aβ1-42, and α-synuclein. In the present study, we expand on these findings, demonstrating that among 13 Prevotella species tested, P. corporis robustly activates the heat shock response (HSR) and confers conserved aggregate-suppressing activity in Drosophila melanogaster. We further demonstrate that transient exposure to P. corporis results in the activation of protective stress pathways and promotes disaggregation of existing intestinal polyQ aggregates in C. elegans, leading to a general enhancement of global proteostasis. This is supported by significantly improved survival and enhanced thermotolerance. Together, our findings reveal a beneficial niche for P. corporis in activating the HSR to enhance organismal proteostasis and support a microbe-mediated gut-proteostasis axis. This work underscores the therapeutic potential of targeting the gut microbiota for the management of PCDs, highlights the importance of species-level resolution in microbiome studies, and supports the emerging view of the intestine as a proteostasis-modulating organ.

Keywords:  Gut Microbiota; Gut-proteostasis Axis; Heat Shock Response; Prevotella corporis; Protein Conformational Diseases; Proteostasis

DOI:  https://doi.org/10.1016/j.cstres.2026.100150
J Neurochem. 2026 Feb;170(2): e70380

Amyloid β-Cholesterol Interplay: Removal of Cholesterol From the Membranes to Catalyze Aggregation and Amyloid Pathology.

Rishiram Baral, Ruan van Deventer, Yuri L Lyubchenko.

  The interplay between the cholesterol metabolism and assembly of Aβ42 (the 42-residue form of the amyloid-β peptide) peptides in pathological aggregates is considered one of the major molecular mechanisms in the development of Alzheimer's disease (AD). Numerous in vitro studies led to the finding that high cholesterol levels in membranes accelerate the production of Aβ aggregates. The molecular mechanisms explaining how cholesterol localized inside the membrane bilayer catalyzes the assembly of Aβ aggregates above the membrane remain unknown. We addressed this problem by combining different AFM modalities, including imaging and force spectroscopy, with fluorescence spectroscopy. Our combined studies revealed that Aβ42 was capable of removing cholesterol from the membrane. Importantly, physiologically low concentrations of Aβ42 demonstrate such ability. Extracted cholesterol interacts with Aβ42 and accelerates its on-membrane aggregation, which is a molecular mechanism explaining how cholesterol embedded in the membrane accelerates Aβ42 aggregation. The discovered ability of Aβ42 to remove cholesterol from membranes resulted in three major AD-related events. First, free cholesterol catalyzes the assembly of Aβ42 in aggregates, which is the mechanism by which physiologically important Aβ42 monomers are converted into their pathological form. Second, the release of cholesterol from membranes leads to its accumulation in the brain, which is one of the risk factors associated with disease development and progression. Third, cholesterol depletion decreases membrane stiffness, which can result in deterioration of the function of membrane-bound proteins, such as dendritic spine degeneration and, ultimately, synapse loss, a common pathological feature of AD.

Keywords:  AFM; Alzheimer's disease; Aβ42; amyloid beta; cholesterol; membranes; protein aggregation

DOI:  https://doi.org/10.1111/jnc.70380
Int J Mol Sci. 2026 Feb 05. pii: 1592. [Epub ahead of print]27(3):

Nrf2-Activating Natural Compounds in Neurodegenerative Diseases: Targeting Oxidative Stress and Protein Aggregation.

Lucia Chico, Erika Schirinzi, Linda Balestrini, Maico Polzella, Gabriele Siciliano.

  Neurodegenerative diseases (NDs) are among the leading causes of disability and mortality worldwide and are characterized by multifactorial pathogenesis involving interconnected mechanisms, such as oxidative stress, protein misfolding and aggregation, neuroinflammation, and mitochondrial dysfunction. Dysregulation of transcription factors, governing cellular defense responses, particularly nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of antioxidant and proteostatic pathways, plays a critical role in neurodegenerative processes. Currently, available pharmacological treatments for NDs are largely symptomatic, as no disease-modifying therapies exist. Natural bioactive compounds have emerged as promising multi-target agents, demonstrating antioxidant, anti-aggregative, and anti-apoptotic properties, frequently mediated through activation of the Nrf2 signaling pathways. These compounds may represent valuable supportive strategies alongside conventional drug treatments, potentially contributing to the modulation of multiple pathogenic mechanisms. This review summarizes key oxidative stress- and protein aggregation-driven mechanisms underlying Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. It further examines the neuroprotective potential of plant-, fungi-, and marine-derived natural compounds, with particular emphasis on Nrf2 activation. Beyond redox regulation, the broader role of Nrf2 in maintaining proteostasis is discussed. Overall, the review highlights Nrf2-inducing nutraceuticals as promising complementary, multi-target approaches for neuroprotection in NDs.

Keywords:  Nrf2; fungi; marine organisms; neurodegeneration; oxidative stress; plant polyphenols; protein aggregation

DOI:  https://doi.org/10.3390/ijms27031592
bioRxiv. 2026 Feb 05. pii: 2026.02.03.703542. [Epub ahead of print]

Gangliosides GM3 And GD3 Modulate Insulin Aggregation Pathways and Reduce Cytotoxicity Through Structural Remodeling.

Nazifa Tasnim Ahmad, Jhinuk Saha, Yimin Mao, Robert Silvers, Zaid Abulaban, Joshua Mysona, Ayyalusamy Ramamoorthy.

Insulin amyloid aggregation is a key pathological and pharmaceutical concern, particularly in the context of Type-2 Diabetes (T2D), where amyloid deposition of protein can impair therapeutic efficacy and contribute to cell death leading to local tissue damage. Although gangliosides-glycosphingolipids containing sialic acid residues-are known to modulate amyloid formation in neurodegenerative disorders, their influence on insulin aggregation remains largely unexplored. In this study, we investigate the effects of gangliosides GM3 and GD3 on insulin aggregation. Using Thioflavin-T (ThT) based fluorescence kinetics, Fourier Transform Infrared (FTIR) spectroscopy, Circular Dichroism (CD) spectroscopy, Small Angle X-ray Scattering (SAXS), Nuclear Magnetic Resonance (NMR) spectroscopy, and Transmission Electron Microscopy (TEM), the aggregation pathway, changes in the secondary structure and morphology of insulin aggregates have been characterized. Our results show that both GM3 and GD3 lipids accelerated insulin aggregation in a concentration-dependent manner while steering the pathway away from classical fibril formation, producing short, beaded structures distinct from the extended fibrils observed under lipid-free conditions. CD and FTIR data analyses revealed that insulin in the presence of gangliosides formed non-fibrillar intermediates with distinct secondary structures: β-sheet-rich globular clusters in presence of GD3 and α-helical intermediates in GM3-treated samples. Cytotoxicity assays further demonstrated that ganglioside-induced aggregates are significantly less toxic to cells when compared to insulin-only aggregates. Furthermore, ganglioside-bound insulin oligomers retain seeding capacity, suggesting that they can nucleate further aggregation despite their non-fibrillar morphology. These findings underscore the role of gangliosides in modulating insulin amyloid polymorphism and toxicity, offering new insights into their potential impact on the pathology of T2D and treatment strategies.
Abstract Figure:
Highlights: Gangliosides GD3 and GM3 accelerate insulin aggregation, forming non-fibrillar assemblies.Ganglioside-bound insulin aggregates are less cytotoxic than fibrillar aggregates.Despite altered morphology, ganglioside-bound aggregates retain seeding ability.

DOI: https://doi.org/10.64898/2026.02.03.703542
Commun Chem. 2026 Feb 11.

Scaffold-client behavior and structural organization in multicomponent protein condensates as revealed by studying tau/TDP-43 droplets.

Vitor Ulisses Monnaka, Brandon Shipley, Solomiia Boyko, Patricia Maria de Carvalho Aguiar, Michael Hinczewski, Witold K Surewicz.

Liquid-liquid phase separation (LLPS) is known to modulate pathological aggregation of proteins implicated in neurodegenerative diseases, such as tau and TDP-43. While LLPS mechanisms of individual proteins are well characterized, much less is known about phase behavior of multicomponent protein systems. Here, we investigated the LLPS behavior of mixtures of tau and TDP-43 low complexity domain (LCD), two proteins known to co-aggregate in Alzheimer's disease. We found that, depending on the concentration, each protein can function either as a scaffold (driving condensate formation) or as a client (passively recruited into condensates formed by the other). Notably, scaffold-client roles can be modulated by selectively inhibiting the interactions driving LLPS: electrostatic for tau, and hydrophobic for TDP-43 LCD. A striking feature of this system is the formation of a tau "halo" around TDP-43 LCD droplets, which coarse-grained simulations reveal to arise from tau's amphiphilic organization at condensate interfaces. Together, these findings provide molecular-level insights into the general principles governing the assembly and organization of multicomponent protein condensates.

DOI: https://doi.org/10.1038/s42004-026-01933-8
bioRxiv. 2026 Jan 27. pii: 2026.01.27.701787. [Epub ahead of print]

Pathological TDP-43 filaments accumulate at synapses and cause synaptic dysfunction.

Renren Chen, Imogen Stockwell, Jessica C Pierce, Sew-Yeu Peak-Chew, Melissa Huang, Kathy Newell, Bernardino Ghetti, Michael A Cousin, Ingo H Greger, Benjamin Ryskeldi-Falcon.

The assembly of TAR DNA-binding protein 43 (TDP-43) into amyloid filaments within neurons is a hallmark of multiple neurodegenerative diseases, including motor neuron diseases (MND), frontotemporal dementias (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). These diseases result from the deterioration and loss of neurons, with synaptic dysfunction and neuronal hyperexcitability being prominent early events. Pathogenic mutations in the TDP-43 gene, TARDBP , that promote filament formation have established a causal role for TDP-43 assembly in neurodegenerative diseases. However, the molecular mechanisms underlying filament accumulation and their contribution to neurodegeneration are poorly understood. TDP-43 filaments can propagate between neurons in a prion-like manner, which may underlie the progressive spread and accumulation of TDP-43 pathology in disease. Here, we studied early stages of TDP-43 filament accumulation following internalisation of patient-derived TDP-43 filaments by mouse and human cortical neurons. Using proximity labelling, we identified molecular environments and putative interactions of TDP-43 filaments. We found that TDP-43 filaments accumulated at synapses, particularly in proximity to the presynaptic active zone, which we confirmed in FTD patient brain sections. Electron cryo-tomography (cryo-ET) directly visualised abundant TDP-43 filaments spanning the presynaptic cytoplasm in situ , which contacted synaptic vesicles and the plasma membrane. Functional measurements revealed that the accumulation of TDP-43 filaments led to presynaptic dysfunction and subsequent neuronal hyperexcitability. These findings suggest that synapses are a major early site of TDP-43 filament accumulation, relevant to their propagation, and directly link TDP-43 filament gain of function to synaptic dysfunction.

DOI: https://doi.org/10.64898/2026.01.27.701787
bioRxiv. 2026 Jan 27. pii: 2026.01.26.701882. [Epub ahead of print]

Dynamic conformational ensembles of soluble Tau encode neuronal toxicity prior to aggregation.

Florian Georgescauld, Sonia Okekenwa, Tanner Boyd, Cameron Donahue, Noe Quittot, John R Dickson, Zhanyun Fan, Scott Brady, Craig Blackstone, Bradley Hyman, Yuyu Song.

Tau aggregation is a defining feature of Alzheimer's disease and related tauopathies, yet the conformational states of Tau in neurons prior to aggregation remain poorly understood. Existing structural models are derived largely from fibrillar assemblies and provide limited insight into the dynamic, soluble Tau species that initiate pathology. Here, we combine hydrogen-deuterium exchange mass spectrometry with super-resolution imaging and neuronal models to define the conformational ensemble of soluble Tau under physiological and disease-relevant conditions. We show that soluble Tau populates distinct, dynamic conformations characterized by regional stabilization and long-range intramolecular interactions that are invisible to fibril-based structures. Disease-associated perturbations selectively remodel these conformational ensembles, exposing aggregation-prone regions and altering Tau subcellular organization in neurons. Notably, these Tau species inhibit axonal transport, which is essential for neuronal health, linking specific ensemble states to neuronal toxicity. These findings establish soluble Tau conformation as a dynamic, regulatable state that precedes aggregation and encodes disease relevance. By defining the structural logic of Tau before fibril formation, this work provides a framework for understanding early tauopathy mechanisms and for targeting Tau pathology at its earliest stages.
SUMMARY: Tau pathology is a hallmark of Alzheimer's disease (AD) and related dementias (ADRDs). Although Tau is often described as intrinsically disordered, it is a dynamic protein with distinct but poorly defined conformations. Here we conduct a systematic time-resolved structure-function analysis of normal and pathologic Tau, including hyperphosphorylated, mutant Tau, and posttranslational-modification-mimetic Tau. To characterize dynamic conformational changes of Tau, we combined state-of-the-art hydrogen deuterium exchange mass spectrometry with structured illumination microscopy, demonstrating a novel Tau-MT binding mode: "dynamic oscillation". To correlate Tau structure with neuronal function, we evaluated axonal transport as a sensitive readout of neuronal health. Many toxic Tau forms share a common signature of increased exposure of the N-terminal phosphate activating domain (PAD) in vitro and in vivo . Aberrant exposure of PAD correlates with Tau pathology and axonal transport defects. Tau phosphorylation at S262 alone is sufficient to alter Tau-microtubule interactions beyond R1-R4 motifs, globally changing Tau conformation, disrupting "dynamic oscillation" on MTs, and inhibiting axonal transport. Frontotemporal dementia-associated P301L-Tau remains associated with microtubules but also inhibits axonal transport. Our results reveal a well-defined conformation of soluble WT Tau in neurons and its highly dynamic interaction with microtubules, altered by AD/ADRD-Tau forms. Our multidisciplinary approach comprising biochemical manipulations, innovative MS tools, advanced microscopy, cellular assays, and mouse and human data pair Tau conformations with distinct neuronal functions and pathologies in health and disease.

DOI: https://doi.org/10.64898/2026.01.26.701882
bioRxiv. 2026 Jan 29. pii: 2026.01.28.702105. [Epub ahead of print]

A HaloTag-4R-Tau Pulse-Chase Sensor Reveals Neddylation Inhibition Promotes Degradation of Tau in iNeurons.

Qiang Xiao, Zi Gao, Seth Allen, Danny Garza, Richard I Morimoto, Jeffery W Kelly.

Tau accumulation is a central driver of neurodegenerative diseases, yet strategies to promote its clearance remain limited. We developed a HaloTag-4R-Tau sensor in human iPSC-derived neurons (iNeurons) that enables sensitive monitoring the kinetics of both lysosomal partitioning and overall cellular turnover of tau. Using this sensor, we screened a small collection of small-molecule modulators of proteostasis network function and identified Neddylation inhibition by Pevonedistat as a robust promoter of soluble tau degradation. Mechanistic analysis including proteomic profiling revealed that Neddylation inhibition hastens HaloTag-Tau clearance via compensatory activation of a proteasome-dependent pathway(s) as well as the autophagy-lysosome pathway. Our findings establish a powerful tool for probing tau homeostasis and highlight Neddylation inhibition as a potential therapeutic approach for enhancing both proteasome and lysosome-mediated tau clearance in tauopathies.

DOI: https://doi.org/10.64898/2026.01.28.702105
Cells. 2026 Jan 27. pii: 241. [Epub ahead of print]15(3):

Big Tau: Structure, Evolutionary Divergence, and Emerging Roles in Cytoskeletal Dynamics and Tauopathies.

Itzhak Fischer, Peter W Baas.

  Tau proteins are microtubule-associated proteins that regulate axonal structure, dynamics, and transport, and their dysregulation underlies several neurodegenerative diseases. The MAPT gene produces multiple tau isoforms through alternative splicing, including the high-molecular-weight isoform known as Big tau, which contains an insert of the large 4a exon of approximately 250 amino acids. Big tau is predominantly expressed in neurons of the peripheral nervous system (PNS), cranial motor nuclei, and select neurons of the central nervous system (CNS) such as the cerebellum and brainstem. Developmental expression studies indicate a switch from low-molecular-weight isoforms of tau to Big tau during axonal maturation, suggesting that Big tau optimizes cytoskeletal dynamics to accommodate long axonal projections. Comparative sequence and biophysical analyses show that the exon-4a insert is highly acidic, intrinsically disordered, and evolutionarily conserved in its length but not its primary sequence, implying a structural role. Emerging modeling and in vitro assays suggest that the extended projection domain provided by the exon-4a insert spatially and electrostatically shields the aggregation-prone PHF6 and PHF6* motifs in tau's microtubule-binding domain, thereby reducing β-sheet driven aggregation. This mechanism may explain why tauopathies that involve aggregation of tau have little effect on the PNS and specific regions of the CNS such as the cerebellum, where Big tau predominates. Transcriptomic and proteomic data further suggest that alternative Big tau variants, including 4a-L, are expressed in certain cancerous tissues, indicating broader roles in cytoskeletal remodeling beyond neurons. Despite its putative anti-aggregation properties, the physiological regulation, interaction partners, and in vivo mechanisms of Big tau remain poorly defined. This review summarizes what is known about Big tau and what is missing toward a better understanding of how expansion via inclusion of exon 4a modifies tau's structural and functional properties. Our purpose is to inspire future studies that could lead to novel therapeutic strategies to mitigate tau aggregation in neurodegenerative diseases.

Keywords:  evolutionary conservation; exon 4a; hydrophobicity; microtubule-associated protein; neurodegeneration; neurons; protein aggregation; tau

DOI:  https://doi.org/10.3390/cells15030241
Front Mol Neurosci. 2026 ;19 1748434

Multilayer modulation of the proteasome: new strategies for neuroprotection.

Maxim Sokolov, Hiroaki Taniguchi, Jonasz Jeremiasz Weber.



Keywords:  20S proteasome; Nrf1 (NFE2L1); neurodegeneration; neuronal proteostasis; proteaphagy; proteasome regulation; transcriptional control; xenogeneic proteostasis

DOI:  https://doi.org/10.3389/fnmol.2026.1748434
FASEB J. 2026 Feb 28. 40(4): e71572

TDP-43 Mediates Autophagic Degradation of Yki by Stabilizing Ref(2)P in Drosophila.

Dongyue Liu, Yufang Xu, Haochuan Wang, Shuai Huang, Shuangxi Li.

  The transcriptional co-activator Yki, the central effector of the Hippo signaling pathway, plays essential roles in regulating tissue growth, regeneration, and tumorigenesis. Although upstream signaling mechanisms controlling Yki activity have been extensively characterized, the molecular mechanisms that govern Yki protein homeostasis remain incompletely understood. In this study, we identify TAR DNA-binding protein 43 (TDP-43) as a critical regulator of Yki proteostasis and demonstrate that stabilization of the autophagic receptor Ref(2)P is indispensable for TDP-43-mediated Yki turnover. Our findings reveal that TDP-43 elevates Ref(2)P levels through two distinct mechanisms. At the post-translational level in the cytoplasm, TDP-43 disrupts the interaction between Ref(2)P and the kinase Dco, thereby preventing phosphorylation-dependent proteasomal degradation of Ref(2)P. At the post-transcriptional level in the nucleus, TDP-43 promotes Ref(2)P mRNA stability by interacting with the nuclear m6A reader protein Ythdc1, which facilitates recognition of N6-methyladenosine (m6A)-modified Ref(2)P transcripts and protects them from decay. Together, these findings delineate a dual regulatory mechanism by which TDP-43 controls Ref(2)P abundance and Yki proteostasis, providing new insights into the fine-tuning of Hippo pathway activity.

Keywords:   Drosophila melanogaster ; Ref(2)P; TDP‐43; Yki

DOI:  https://doi.org/10.1096/fj.202503852RR