bims-proned 2026-03-29 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–03–29
twenty papers selected by
Verena Kohler, Umeå University

The anti-diabetic drug acarbose modulates the nucleation dependent amyloid fibrillation of wild-type α-synuclein.
SYNGR3 Accelerates α-Synuclein Aggregation and Neurodegeneration in Parkinson's Disease.
Unfolded proteins and aggregates: The role of proteostasis in pseudoexfoliation pathology.
A quantitative cell-based reporter links TDP-43 aggregation and dysfunction to define pathogenic mechanisms.
Protein phosphatase 2A methylation state impacts α-synucleinopathy in mouse models.
Involvement of 75NTR extracellular domain in rotenone-induced Parkinson's disease cell models.
Tau Protein Aggregation Inhibitors-Therapeutic Strategy for Concurrent Tau and Amyloid Aggregation Inhibition.
Structural and Mechanistic Heterogeneity of the Phase Separation and Aggregation of Full-Length TDP-43 is Governed by Environmental Conditions.
Tau catalyzes amyloid-β aggregation and toxicity in a polymorph-dependent manner.
Targeting Autophagy with Bioactive Compounds: Therapeutic Potential in Neurodegenerative Disorders.
Tyr39 Phosphorylation of α-Synuclein Accelerates Heterotypic Aggregation and Drives Toxic Amplification.
Chemical and Molecular Strategies in Restoring Autophagic Flux in TDP-43 Proteinopathy.
Residue-Specific Modulation of Aggregation-Associated Interactions by Spermine in Tau, α‑Synuclein, and Aβ40.
Cysteines are critical determinants of spontaneous and seeded tau aggregation in cells.
Scalable assay to identify inhibitors of prion-like propagation of protein misfolding as potential therapeutics for neurodegeneration.
Systems-level organization of extracellular proteostasis.
K16F/E22F Mutation Promotes Oligomerization and Alters β-Sheet Topology of Aβ16-22 Peptides: Insights from Molecular Dynamics Simulations.
Chaperone proteins protect against desmin fragment amyloid aggregation.
Drug screening for α-synuclein aggregation inhibitors via multimodal graph neural network.
The brainstem in neurodegenerative diseases.

J Comput Aided Mol Des. 2026 Mar 26. pii: 85. [Epub ahead of print]40(1):

The anti-diabetic drug acarbose modulates the nucleation dependent amyloid fibrillation of wild-type α-synuclein.

Almas Akhtar, Payal Singh, Nikita Admane, Abhinav Grover.

  Parkinson's disease (PD) is a prevalent, age-associated neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation of intracellular Lewy bodies, primarily composed of aggregated α-synuclein protein. In the present study we have examined Acarbose, an anti-diabetic drug, as a potential structure-based inhibitor of α-synuclein aggregation to advance therapeutic strategies for synucleinopathies. Using an integrated computational and experimental approach, we demonstrate that acarbose binds to key amyloidogenic residues within the amyloid core of α-synuclein, disrupting native hydrogen bonds, reduces β-sheet propensity and stabilizes the protein in an extended, aggregation-resistant conformation. Acarbose significantly affects α-synuclein fibrillation, substantiated by reducing the Thioflavin T fluorescence by 67.29%, 81.13%, and 90.36% at 20, 60, and 100 µM concentrations, respectively. The dose dependent increase in lag phase of amyloid fibrillation kinetics in presence of Acarbose further suggests that it interferes with the primary nucleation event. Further structural characterization using CD spectroscopy, high-end microscopy and dynamic light scattering confirmed that Acarbose inhibits the structural transitions of the protein into mature cross-β-sheet-rich amyloid fibrils. Collectively, these results establish the strong potential of Acarbose for repurposing against Parkinson's disease. Its targeted modulation of α-synuclein aggregation also positions it as a promising scaffold for the design of next-generation amyloid inhibitors.

Keywords:  Acarbose; Aggregation inhibitor; Anti-diabetic drug; Parkinson’s disease; REMD simulations; α-synuclein

DOI:  https://doi.org/10.1007/s10822-026-00790-w
CNS Neurosci Ther. 2026 Mar;32(3): e70842

SYNGR3 Accelerates α-Synuclein Aggregation and Neurodegeneration in Parkinson's Disease.

Xin Wang, Jiaolong Yang, Ziku Wang, Zhichao Liu, Wei Tan, Zhentao Zhang.

   BACKGROUND AND AIMS: The aggregation of α-synuclein (α-syn) is a central event in Parkinson's disease (PD) pathogenesis. However, the cellular factors that initiate and accelerate the process are not fully understood. Synaptogyrin-3 (SYNGR3) is a synaptic vesicle protein whose role in α-syn pathology remains unexplored. This study investigated whether SYNGR3 is a key factor triggering the pathological process of PD.
METHODS: This study investigated the expression of SYNGR3 in the brains of transgenic A53T α-syn mutant mouse line M83 (TgA53T) PD model mice using Western blot. The direct interaction between SYNGR3 and α-syn was assessed by GST pull-down assays. This study examined the effect of SYNGR3 on α-syn aggregation kinetics and fibril stability in vitro through the thioflavin T (Th T) assays and proteinase K (PK) digestion. By overexpressing or knocking down SYNGR3 in HEK-293 cells stably transfected with α-syn, primary neurons, and TgA53T mice, the effects of enhanced or deficient function of SYNGR3 on α-syn pathology, synaptic integrity, mitochondrial function, and motor behavior were evaluated.
RESULTS: SYNGR3 levels were significantly elevated in an age-dependent manner in the striatum of TgA53T mice. The study found that SYNGR3 directly interacts with the central region of α-syn and accelerates its aggregation into fibrils that are more resistant to PK digestion. Overexpression of SYNGR3 exacerbated α-syn aggregation, synaptic protein loss, mitochondrial dysfunction, and apoptosis in cellular models. In vivo, SYNGR3 intensified α-syn pathology, dopaminergic neurodegeneration, and PD-like motor deficits. Conversely, knockdown of SYNGR3 effectively alleviated these pathological and behavioral impairments.
CONCLUSION: This study identifies SYNGR3 as a novel and critical promoter of α-syn aggregation and neurotoxicity. These findings establish SYNGR3 as a key contributor to PD pathogenesis and highlight its potential as a therapeutic target for intervention.

Keywords:  mitochondrial dysfunction; parkinson's disease; protein aggregation; α‐synuclein

DOI:  https://doi.org/10.1002/cns.70842
Mol Vis. 2025 ;31 463-484

Unfolded proteins and aggregates: The role of proteostasis in pseudoexfoliation pathology.

Bushra Hayat, Debasmita Pankaj Alone.

BACKGROUND: Proteostasis impairment is central to cellular dysfunction in protein aggregation disorders such as Alzheimer disease, Parkinson disease, and age-related macular degeneration. Pseudoexfoliation (PEX), a systemic age-related disorder and a leading cause of secondary glaucoma, is increasingly recognized as a protein aggregation disease. It is characterized by the deposition of pseudoexfoliative material (PEXM) in ocular tissues, leading to elevated intraocular pressure and optic neuropathy.
OBJECTIVE: This review synthesizes current evidence on the role of proteostasis failure in PEX pathogenesis, with a focus on molecular mechanisms, stress response pathways, and potential therapeutic interventions.
METHODS: We conducted a comprehensive literature review of studies examining proteostasis mechanisms in PEX. Emphasis was placed on cellular pathways regulating protein synthesis, folding, and degradation, including the unfolded protein response (UPR), ubiquitin-proteasome system (UPS), and autophagy, as well as environmental and aging-related triggers of proteotoxic stress.
RESULTS: Evidence indicates that chronic proteotoxic stress, arising from aging, oxidative damage, and environmental influences, disrupts the proteostasis network (PN). Dysregulation of ER stress signaling, cytosolic stress responses, and protein degradation pathways contributes to the accumulation of misfolded proteins and extracellular matrix deposits in ocular tissues. These molecular alterations underlie disease onset and progression in PEX syndrome (PEXS) and PEX glaucoma (PEXG).
CONCLUSIONS: Proteostasis dysfunction plays a pivotal role in PEX pathogenesis by promoting protein misfolding, aggregation, and extracellular deposition. Targeting the proteostasis network, through modulation of stress responses and enhancement of degradation pathways, represents a promising therapeutic strategy for PEXS and PEXG.
PLoS Biol. 2026 Mar;24(3): e3003662

A quantitative cell-based reporter links TDP-43 aggregation and dysfunction to define pathogenic mechanisms.

Lohany Dias Mamede, Miwei Hu, Jaime Vaquer-Alicea, Amanda R Titus, Patricia M Passos, Erica Lantelme, Rachel L French, Paige A Kirschner, Marc I Diamond, Timothy M Miller, Yuna M Ayala.

TDP-43 pathology is a hallmark of fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43-encephalopathy (LATE). In affected patients, cytoplasmic TDP-43 aggregates are accompanied by disruption of its normal nuclear localization and function. Because TDP-43 is an RNA binding protein that controls transcript processing, including repression of cryptic exon splicing, its loss leads to dysregulation of gene expression. Despite its central significance in disease, the connection between TDP-43 aggregation and dysfunction remains poorly understood, and models to study the underlying mechanisms are limited. Here, we characterize a robust and quantitative cell-based reporter that captures both aggregation and the resulting loss of function. Using this human biosensor cell line, we show that aggregation initiated by prion-like seeding drives progressive depletion of nuclear TDP-43 and induces signature features of diminished TDP-43 activity, such as increased DNA damage and activation of cryptic exon splicing. We find that aggregate seeding also induces cryptic exon splicing in human neurons implying that this pathological link extends to disease-relevant models. The seeding model provides a platform for dissecting mechanisms that underlie TDP-43 pathology and for identifying factors that modulate the aggregation-to-dysfunction transition. Our data shows that aggregate seeding impacts TDP-43 autoregulation, initiating a toxic feed-forward mechanism that disrupts TDP-43 homeostasis. Furthermore, reducing ataxin-2 levels decreases aggregation and restores TDP-43 activity. Together, these findings reveal a molecularly guided strategy to directly impact TDP-43 activity by decreasing its misfolding and aggregation, highlighting approaches to prevent TDP-43 dysfunction and mitigate toxicity under pathological conditions.

DOI: https://doi.org/10.1371/journal.pbio.3003662
Cell Death Discov. 2026 Mar 24.

Protein phosphatase 2A methylation state impacts α-synucleinopathy in mouse models.

Santhosh Maddila, Kambiz Hassanzadeh, Jun Liu, Jie Zhang, Faheem Ullah, Russell E Nichols, M Maral Mouradian.

The accumulation of aggregated alpha-Synuclein (α-Syn) in Lewy bodies and Lewy neurites is a hallmark of Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB), and phosphorylation of α-Syn at Ser129 is a key pathological marker in synucleinopathies. The heterotrimeric enzyme protein phosphatase 2A (PP2A), and specifically its B55α containing isoform, which dephosphorylates phospho-S129-α-Syn, is regulated through methylation of its catalytic C subunit, a process that is controlled by the opposing activities of leucine carboxyl methyltransferase 1 (LCMT-1) and protein phosphatase methylesterase 1 (PME-1). Postmortem studies show decreased LCMT-1 and increased PME-1 levels in PD and DLB brains, leading to reduced PP2A activity and α-Syn hyperphosphorylation. To investigate the pathophysiological relevance of this regulatory axis, we employed genetically modified mice in two models of synucleinopathy, transgenic animals and intrastriatal α-Syn preformed fibrils (PFF) injections. A battery of behavioral tests was conducted to assess motor and cognitive function, followed by brain analyses quantifying phosphorylated α-Syn aggregates, neuronal toxicity, and neuroinflammatory responses, thereby evaluating how modulation of this axis influences α-Syn pathology. Overexpression of PME-1 in forebrain neurons exacerbated α-Syn pathology, characterized by increased Ser129 phosphorylation and aggregation, as well as neurodegeneration and neuroinflammation, accompanied by significant motor impairments. These effects were observed both in transgenic mice co-expressing PME-1 and human α-Syn at 9 months of age, and in PME-1 overexpressing mice six months after intrastriatal injection of α-Syn PFF. In contrast, LCMT-1 overexpression reduced α-Syn phosphorylation and aggregation, and provided robust neuroprotection, leading to improved motor outcomes in both synucleinopathy models. These findings underscore the critical role of PP2A methylation dynamics in regulating α-Syn toxicity. Accordingly, targeting the PP2A methylation machinery represents a promising therapeutic strategy to mitigate α-Syn-induced neurodegeneration and slow the progression of synucleinopathies.

DOI: https://doi.org/10.1038/s41420-026-03045-7
Neuroreport. 2026 Apr 01. 37(6): 247-257

Involvement of 75NTR extracellular domain in rotenone-induced Parkinson's disease cell models.

Yifei You, Anyan Ren, Nan Wang, Fang Chen, Xianzhi Wang, Chen Li, Hongcai Wang.

   OBJECTIVE: While the p75 neurotrophin receptor (p75NTR) is critically implicated in the aggregation of α-synuclein (α-syn), a defining pathological hallmark of Parkinson's disease, the distinct functional contributions of its structural domains remain largely unresolved.
METHODS: To investigate this, we employed a rotenone-induced cellular Parkinson's disease model utilizing SH-SY5Y neuroblastoma cells transfected with plasmids encoding specific p75NTR truncation mutants.
RESULTS: Overexpression of a mutant representing the p75NTR extracellular domain (HA-p75Δ151, lacking residues 277-427) significantly exacerbated both α-syn expression levels and its aggregation phenotype. This effect is potentially attributable to the aberrant activation of caspase-1. Conversely, unlike full-length p75NTR which enhanced α-syn ubiquitination, the HA-p75Δ151 truncation failed to modulate ubiquitination dynamics. Furthermore, expression of this extracellular domain fragment induced cell cycle dysregulation and promoted cell death.
CONCLUSION: These findings delineate the p75NTR extracellular domain-induced α-syn proteotoxic stress. This domain-specific mechanism advances our understanding of Parkinson's disease pathogenesis and highlights the therapeutic potential of targeting specific p75NTR domains.

Keywords:  Parkinson’s disease; p75 neurotrophin receptor (p75NTR); ubiquitination; α-synuclein

DOI:  https://doi.org/10.1097/WNR.0000000000002258
Biomedicines. 2026 Feb 26. pii: 522. [Epub ahead of print]14(3):

Tau Protein Aggregation Inhibitors-Therapeutic Strategy for Concurrent Tau and Amyloid Aggregation Inhibition.

Thomas Gabriel Schreiner, Romeo Cristian Ciobanu, Oliver Daniel Schreiner.

  Tau protein, a microtubule-associated protein widely distributed in the central nervous system, aggregates abnormally and forms neurofibrillary tangles in neurodegenerative diseases. Particularly in Alzheimer's disease, pathological tau protein aggregates disrupt the structure and function of neurons, triggering other neurodegenerative-related processes such as neuroinflammation and amyloid plaque formation, and finally leading to neuronal death. Several classes of drugs targeting neurofibrillary tangles have recently been studied, with tau protein aggregation inhibitors as a key research direction. In the context of emerging therapeutic perspectives, this review aims to provide an updated, practical overview of currently available tau protein aggregation inhibitors and future research directions. The first part of the manuscript highlights the pathophysiological basics of tau protein aggregation and tau-related changes in neurodegenerative disorders, with a focus on Alzheimer's disease pathology. Subsequently, the most relevant classes of drugs that inhibit tau protein aggregation, including small-molecule inhibitors and natural compounds, are presented, with examples from recent clinical trials. Finally, beyond summarizing established classes of tau aggregation inhibitors, this review places particular emphasis on emerging and comparatively underexplored compounds with dual activity against both tau and amyloid-β pathology. The originality and novelty of this work arise from the systematical analysis of recent preclinical and clinical evidence with a translational, practice-oriented perspective, highlighting mechanistic convergence, repurposing opportunities, and therapeutic combinations that may better reflect the multifactorial nature of neurodegenerative diseases. Thus, this work provides a forward-looking framework for future drug development and identifies promising candidates that may shape the next generation of disease-modifying therapies.

Keywords:  Alzheimer’s disease; curcumin; neurodegeneration; small-molecule inhibitor; tau protein

DOI:  https://doi.org/10.3390/biomedicines14030522
ACS Chem Neurosci. 2026 Mar 23.

Structural and Mechanistic Heterogeneity of the Phase Separation and Aggregation of Full-Length TDP-43 is Governed by Environmental Conditions.

Abhilasha A Doke, Mona S Kirmire, Anjali Jha, Santosh Kumar Jha.

  TAR DNA-binding protein 43 (TDP-43) is an essential physiological protein implicated in several fatal neurodegenerative disorders. Interestingly, the nature of TDP-43 aggregates varies across patients and disease conditions, suggesting an underlying heterogeneity in its self-assembly behavior. In this study, we investigated two native-like states of full-length TDP-43: the native dimer (N form) and the native-like oligomer (O form). These are compact, folded states with similar secondary structures but differ in size. We found that the N and O forms respond differently to external perturbations and form distinct self-assemblies under stress conditions. Under electrostatic stress, both N and O forms undergo phase separation but produce condensates with markedly different morphologies and dynamics. The underlying mechanisms driving their phase separation are different. Under thermal stress, both forms convert into amyloid aggregates, but again with clearly different morphologies, biochemical properties, and aggregation pathways. These results demonstrate that multiple conformations of TDP-43 respond to distinct perturbations by assembling into structurally and mechanistically different higher-order assemblies. Our findings highlight how the interplay among the structural state, solvation environment, and self-assembly mechanism governs the heterogeneity of TDP-43 assemblies, offering new insights into their physiological roles and pathological relevance. This study suggests that the heterogeneity observed in patients associated with TDP-43 aggregation may arise from differences in the cellular stresses experienced by the protein and the corresponding assembly mechanisms engaged.

Keywords:  amyloid-like aggregation; molecular mechanism of phase separation; native-like phase separation; self-assembly

DOI:  https://doi.org/10.1021/acschemneuro.5c01003
Proc Natl Acad Sci U S A. 2026 Mar 31. 123(13): e2532775123

Tau catalyzes amyloid-β aggregation and toxicity in a polymorph-dependent manner.

Michele Mosconi, Chiara Leonardi, Zev Armour-Garb, Beatrice Rocutto, Marten Beeg, Georg Meisl, Lei Ortigosa-Pascual, Luca Broggini, Mario Salmona, Stefano Ricagno, Tuomas P J Knowles, Luisa Diomede.

  Interactions between amyloidogenic proteins are emerging as critical drivers of neurodegenerative diseases. Among others, in Alzheimer's disease (AD) and severe forms of chronic traumatic encephalopathy (CTE), codeposition of tau and amyloid-β (Aβ) leads to worsening of clinical outcomes and disease progression. Despite the importance of such heterotypic interactions, the underlying molecular mechanisms have proven challenging to be established. Here, we investigated the direct interaction between Aβ and tau, combining in vitro reconstruction, and in vivo models. We find that characteristic AD paired helical filament (PHF) and CTE folds catalyze the primary nucleation of Aβ42 in a fold-specific manner with enzyme-like kinetics. In particular, CTE fibrils exhibit the highest catalytic activity and constrain Aβ42 polymorphism, suggesting templating effects. Moreover, PHF and CTE tau fibrils increase Aβ42 toxicity in SH-SY5Y neuroblastoma cells and transgenic Caenorhabditis elegans, preserving fold-dependent reactivities. Our findings shed light on the molecular mechanisms of heterotypic interaction between amyloidogenic proteins in disease-relevant conditions, highlighting the role of amyloid structure and recognition mechanisms as key determinants. These results offer insights into the pathological mechanisms of multiple proteinopathies. The mechanisms described here might be used as a blueprint for structure-based design of new therapeutic agents targeting specific amyloidogenic interactions.

Keywords:  Alzheimer’s disease; amyloid-β; chronic traumatic encephalopathy; protein aggregation; tau

DOI:  https://doi.org/10.1073/pnas.2532775123
Curr Neuropharmacol. 2026 Mar 16.

Targeting Autophagy with Bioactive Compounds: Therapeutic Potential in Neurodegenerative Disorders.

Arun Kumar Singh, Anuradha Kush, Bharat Bhushan, Meenakshi Dhanawat, Pravesh Kumar Sharma.

  Neurodegenerative disorders (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are characterized by the accumulation of misfolded proteins and impaired cellular clearance mechanisms. Autophagy, a critical lysosomedependent degradative pathway, plays a vital role in maintaining proteostasis and neuronal health. Dysregulation of autophagy has been implicated in the pathogenesis of multiple NDs, making it a promising therapeutic target. This review comprehensively examines the molecular mechanisms of autophagy and its dysfunction across major NDs. Furthermore, it highlights the potential of bioactive compounds such as flavonoids, alkaloids, polyphenols, and terpenoids to modulate autophagic flux, thereby promoting the clearance of toxic protein aggregates like amyloid-β, tau, and α- synuclein. Emerging strategies, including nanotechnology-based delivery systems, are also discussed for enhancing the bioavailability and efficacy of these compounds. The evidence suggests that pharmacological or natural induction of autophagy may alleviate neurodegenerative pathology, though context- and stage-specific modulation is essential. This work underscores the therapeutic promise of autophagy-enhancing bioactives and calls for further research into their clinical applications.

Keywords:  Neurodegenerative disorders; alzheimer’s disease; amyotrophic lateral sclerosis; autophagy; bioactive compounds.; parkinson’s disease

DOI:  https://doi.org/10.2174/011570159X408653251130061347
J Am Chem Soc. 2026 Mar 27.

Tyr39 Phosphorylation of α-Synuclein Accelerates Heterotypic Aggregation and Drives Toxic Amplification.

Qinghao Huo, Wei-Han Meng, Xiaohui Wu, Shuoshuo Song, Siyu Zhang, Yin Yang, Xun-Cheng Su, Linqi Shi, Feihe Ma.

c-Abl-mediated Tyr39 phosphorylation of α-synuclein correlates strongly with Parkinson's disease (PD) progression, yet the mechanistic basis of Tyr39-phosphorylated α-synuclein (pY39-α-syn) in synucleinopathies remains elusive. Here, we show that a minor fraction of pY39-α-syn markedly accelerates the aggregation of wild-type α-synuclein (WT-α-syn), overriding the inhibitory effect of Hsc70. Kinetics, continuous-wave electron paramagnetic resonance (EPR), cryo-transmission electron microscopy (cryo-TEM), and [15N,1H]-NMR spectral analyses reveal that pY39-α-syn participates in primary nucleation, generating heterotypic nuclei that promote secondary nucleation predominantly through a fragmentation-based pathway. The resulting heterotypic aggregates are structurally unstable, forming short, preformed fibrillar-like assemblies that facilitate toxic amplification of α-synuclein species. Moreover, more toxic type-B oligomers arise from intermediate aggregates derived from these heterotypic assemblies. Notably, we further show that the heterotypic aggregates possess Fenton-like catalytic activity by binding and stabilizing Fe2+, providing new mechanistic insights into Fe2+-dependent oxidative toxicity during PD progression. Collectively, this study provides a systematic elucidation of how Tyr39 phosphorylation reprograms α-synuclein aggregation toward toxic amplification, offering new insight into PD-related α-synucleinopathies.

DOI: https://doi.org/10.1021/jacs.5c20693
Molecules. 2026 Mar 10. pii: 924. [Epub ahead of print]31(6):

Chemical and Molecular Strategies in Restoring Autophagic Flux in TDP-43 Proteinopathy.

Angelo Jamerlan, John Hulme.

  The cytoplasmic accumulation of TDP-43 aggregates remains a persistent pathological hallmark of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). The cell's natural clearance mechanisms, the Ubiquitin-Proteasome System (UPS) and the autophagy-lysosome pathway (ALP), are hypothesized to fail, at least in part, due to the sequestration of key components of these pathways by pathological TDP-43 species, thereby impairing autophagosome-lysosome fusion and lysosomal competence. Classical autophagic activators (e.g., rapamycin) can initiate upstream steps in the pathway but cannot address downstream flux bottlenecks, limiting their ability to restore effective TDP-43 clearance. This review revisits classical strategies and discusses newer approaches to modulate TDP-43 clearance, including transcription factor EB (TFEB) activators, proteolysis-targeting chimeras (PROTACs), and antisense oligonucleotides (ASOs). We propose that adopting multi-targeting strategies and developing better biomarkers are vital for clinical success.

Keywords:  PROTACs; TDP-43 proteinopathy; amyotrophic lateral sclerosis; autophagic flux; autophagy-lysosome pathway; frontotemporal dementia; neurodegeneration; proteostasis

DOI:  https://doi.org/10.3390/molecules31060924
JACS Au. 2026 Mar 23. 6(3): 2040-2054

Residue-Specific Modulation of Aggregation-Associated Interactions by Spermine in Tau, α‑Synuclein, and Aβ40.

Debasis Saha, Xun Sun, Wangfei Yang, Jinghui Luo, Wenwei Zheng.

  Preventing neurodegenerative diseases associated with intrinsically disordered proteins (IDPs) remains a major challenge due to the lack of a detailed, sequence-level picture of disease-relevant structure formation and the influence of cellular factors that modulate these transitions. Here, we probe spermine (Spm), a +4 charged polyamine abundant in cells, to determine how it reshapes the conformational ensembles and fibril-associated contact propensities of three disease-linked IDPs: the K18 domain of Tau, α-synuclein (αS), and amyloid-β40 (Aβ40). Using long all-atom molecular dynamics simulations across a range of Spm concentrations, we quantify residue-level changes in intrachain contacts relative to native contacts observed in fibrils and corroborate computational predictions with ThT fluorescence assays for Tau constructs. Spm acts in a sequence- and region-specific manner, not simply through the overall net charge. In K18, Spm binds near the fourth microtubule-binding repeat, disrupting intrachain contacts associated with Alzheimer's fibril structures and thereby inhibiting aggregation. In αS, Spm binds mainly to acidic residues in the C-terminal half of the sequence and redistributes intramolecular contacts to enhance aggregation-prone interactions in the central region, providing a residue-level mechanistic basis for previously reported Spm-enhanced αS aggregation. For Aβ40, Spm neutralizes acidic residues near positions 22-24 and shifts intrachain interactions toward its aggregation-prone core, resulting in a net promotion of fibril-like conformations. These divergent effects show that net charge alone cannot predict the polyamine influence on IDPs. Instead, residue-specific binding hotspots and local reweighting of aggregation-linked contacts determine whether Spm promotes or suppresses fibril-like conformations. This combined simulation-experimental framework provides a mechanistic basis for how small molecules reprogram IDP conformational ensembles and suggests principles for designing ligands that exploit similar residue-level modulation.

Keywords:  all-atom molecular dynamics; intrinsically disordered protein; liquid−liquid phase separation; protein aggregation; spermine

DOI:  https://doi.org/10.1021/jacsau.6c00126
bioRxiv. 2026 Mar 16. pii: 2026.03.12.711133. [Epub ahead of print]

Cysteines are critical determinants of spontaneous and seeded tau aggregation in cells.

Parvathy Jayan, Simran Rastogi, Vaibhav Bommareddy, Chad M Dashnaw, Jaime Vaquer-Alicea, Binh An Nguyen, Lorena Saelices, Sarah Shahmoradian, Charles L White, Marc I Diamond, Lukasz A Joachimiak.

The frontotemporal dementia-linked S320F mutation in the microtubule-associated protein tau promotes spontaneous aggregation, yet the structural basis of its amyloidogenesis remains unclear. Using cryo-electron microscopy, we determined the structure of an S320F 295-330 tau fibril composed of parallel chains stabilized by the 306 VQIVYK 311 amyloid motif, with S320F buried in the fibril core and a C322-C322 disulfide linking two protofilaments. Although cysteines are dispensable for fibril formation by isolated peptide fragments in vitro, tau repeat domain constructs containing both C291 and C322 generate more potent seeds in cellular assays. In contrast, the C322S mutation suppresses spontaneous aggregation of S320F tau in cells, and combined C291S and C322S mutations inhibit seeded aggregation in both wild-type and S320F contexts. Systematic alanine mutagenesis coupled with seeding by tauopathy-derived material identifies cysteine residues as critical determinants of tau seeding, comparable in importance to core amyloid motifs. Together, these findings establish cysteines as central chemical regulators of tau aggregation and propagation.

DOI: https://doi.org/10.64898/2026.03.12.711133
Protein Sci. 2026 Apr;35(4): e70535

Scalable assay to identify inhibitors of prion-like propagation of protein misfolding as potential therapeutics for neurodegeneration.

Abhishek Narayan, Krishna Neupane, Michael T Woodside.

  Protein misfolding is linked to many neurodegenerative diseases. In some cases, misfolding can propagate through a prion-like mechanism whereby natively folded molecules are converted into more copies of the misfolded isoform. Prion-like propagation of misfolding is an attractive therapeutic target, but difficulties with assaying conversion directly and simply have severely limited efforts to find drugs targeting conversion of disease-related proteins. Here, we demonstrate a scalable enzymatic assay for testing potential inhibitors of prion-like conversion in superoxide dismutase-1 (SOD1), whose misfolding is linked to amyotrophic lateral sclerosis (ALS). We tested several small-molecule inhibitors of SOD1 aggregation to determine if they also inhibited prion-like conversion. We found that some compounds, like telbivudine and cisplatin, did indeed significantly delay conversion, but others, like baicalein and quercetin, had little effect. Surprisingly, some compounds, like two statins tested, actually accelerated conversion, suggesting that they might act to promote ALS progression. These results underline the fact that conversion and aggregation are distinct biophysical processes. The ability of the assay to identify compounds effective at delaying prion-like conversion holds out promise for applications in future drug discovery efforts that target propagated misfolding specifically.

Keywords:  amyotrophic lateral sclerosis; prion‐like conversion; small‐molecule inhibitors; superoxide dismutase 1

DOI:  https://doi.org/10.1002/pro.70535
Science. 2026 Mar 26. 391(6792): 1332-1338

Systems-level organization of extracellular proteostasis.

Cláudio M Gomes, Michele Vendruscolo.

One defining feature of complex organisms is the ability to maintain protein homeostasis beyond cellular boundaries. We review how extracellular proteostasis is organized as a hierarchical network spanning pericellular, tissue, and systemic tiers. At each tier, secreted chaperones, proteases, vesicles, receptors, immune sentinels, and clearance organs cooperate to recognize, buffer, and eliminate misfolded proteins. Feedback through immune signaling, stress-induced protein secretion, and glymphatic and lymphatic transport adjusts capacity to proteotoxic load. We illustrate how failures in this stratified defense underlie neurodegenerative disorders and systemic amyloidoses, and we highlight strategies that stabilize extracellular proteins, augment clearance pathways, or enhance fluid transport. Viewing extracellular proteostasis as an integrated systems-level network reveals opportunities for combinatorial and preventive therapies.

DOI: https://doi.org/10.1126/science.aed3712
ACS Chem Neurosci. 2026 Mar 23.

K16F/E22F Mutation Promotes Oligomerization and Alters β-Sheet Topology of Aβ16-22 Peptides: Insights from Molecular Dynamics Simulations.

Viet Hoang Man, Xibing He, Taoyu Niu, Lianjin Cai, Fengyang Han, Phuong Nguyen, Junmei Wang.

  Amyloid-β (Aβ) aggregation into toxic oligomers and fibrils is a hallmark of Alzheimer's disease. The Aβ16-22 fragment plays a critical role in the early stages of the aggregation of full-length Aβ peptides. Aggregation of Aβ16-22 is primarily driven by hydrophobic interactions within the LVFF core and electrostatic attraction between flanking residues K16 (+) and E22 (-). To dissect the relative contributions of these forces, we introduced a K16F/E22F double mutation, which eliminates charged residues while enhancing hydrophobicity and aromaticity. This substitution provides a controlled system to evaluate how specific interactions influence aggregation behavior. Using a novel computational protocol, featuring a strategically designed 4-mer system, multiple independent and long-time scale trajectories, and specialized analysis, we directly tracked and comprehensively characterized the oligomerization process. The mutation significantly enhanced both intra- and intermolecular interactions, promoting aggregation. It also altered the oligomerization pathways, as reflected in the distinct distribution across ten possible states formed by four Aβ16-22 peptides. Furthermore, while the wild-type peptide predominantly formed antiparallel β-sheets, the mutant favored parallel and mixed β-sheet arrangements. These results indicated that increased hydrophobicity and aromaticity facilitate more stable and polymorphic aggregation pathways. Our findings highlight the dominant role of hydrophobic interactions in early-stage Aβ aggregation and emphasize the therapeutic potential of targeting hydrophobic hotspots, such as the LVFF core, while accounting for structural polymorphism rather than focusing solely on disrupting electrostatic interactions.

Keywords:  K16F/E22F mutation; amyloid aggregation; amyloid-β peptides; molecular dynamics simulation; oligomerization; β-sheet structure

DOI:  https://doi.org/10.1021/acschemneuro.6c00003
Biophys J. 2026 Mar 23. pii: S0006-3495(26)00222-5. [Epub ahead of print]

Chaperone proteins protect against desmin fragment amyloid aggregation.

Erin M Mulhearn, Ariel M Alperstein.

In desmin-related cardiomyopathy, cellular stresses cause desmin to cleave and aggregate in vivo. Cleaved desmin fragments are amyloidogenic and induce misfolding, aggregation, and amyloid fibril formation of full-length wild type desmin. Alongside this disease condition, cells overexpress αB-crystallin and heat shock protein (HSP) 27 as cardioprotective chaperones. Chaperone proteins may refold, sequester, or disaggregate misfolded or aggregating client proteins. Previously, little was known about the protective influence of chaperone proteins on desmin fragment amyloid formation. Here, we studied the secondary structure changes, kinetics, and morphology of desmin fragment amyloid formation with and without chaperone proteins αB-crystallin and HSP27. We found that both of these proteins prevent or delay amyloid formation in a concentration-dependent manner, but we did not observe amyloid disaggregation. We discovered better chaperone activity by αB-crystallin than HSP27 towards desmin fragment, correlated to increased binding sites between αB-crystallin and desmin fragment. Our interaction studies demonstrated that monomers or amorphous oligomers were likely reversibly captured by these chaperone proteins whereas desmin fragment amyloid fibrils were likely irreversibly capped by chaperone proteins. Overall, αB-crystallin and HSP27 recognized and interacted with both desmin fragment monomer and desmin fragment amyloid at distinct sites to prevent further amyloid formation.

DOI: https://doi.org/10.1016/j.bpj.2026.03.038
Brief Bioinform. 2026 Mar 01. pii: bbag118. [Epub ahead of print]27(2):

Drug screening for α-synuclein aggregation inhibitors via multimodal graph neural network.

Tingle Gu, Zixu Ran, Wenyin Li, Xudong Guo, Bo Li, Fuyi Li, Cangzhi Jia.

  The pathological aggregation of α-synuclein (α-syn) constitutes a pivotal hallmark in the progression of neurodegenerative disorders, including Parkinson's disease, underscoring the imperative need for identifying site-specific ligands. This study presents, for the first time, an advanced deep learning framework specifically designed for the prediction of molecular properties associated with α-syn. The framework integrates graph-based contextual attention mechanisms, structural feature aggregation protocols, and dual-channel feature integration, complemented by a composite regularization strategy that synergizes mean squared error minimization, Kullback-Leibler divergence-induced latent space regularization, and L2 norm penalization, thereby delivering outstanding predictive accuracy on the independent test dataset with MSE of 0.1812. Mechanistic insights derived from GNNExplainer analysis and molecular docking studies (PDB: 6A6B) elucidated that aromatic ring systems (benzene ring significance: 0.737) and hydrogen bond donor groups (amino group significance: 0.438) play critical roles in mediating high-affinity ligand-receptor interactions through π-π stacking within the hydrophobic pocket formed by Val82 and Ala89 residues, as well as directed hydrogen bonding involving catalytic residues Ser42 and Lys45. These findings not only enhance the understanding of inhibitor mechanisms but also establish a novel framework for the preliminary screening of small-molecule therapeutics, thereby laying a rigorous groundwork for structure-guided drug optimization and rational molecular design.

Keywords:  QSAR; composite regularization; dual-channel feature fusion; graph contextual attention; α-synuclein

DOI:  https://doi.org/10.1093/bib/bbag118
Handb Clin Neurol. 2026 ;pii: B978-0-443-15736-3.00017-2. [Epub ahead of print]216 201-212

The brainstem in neurodegenerative diseases.

Lea Tenenholz Grinberg.

  The brainstem, despite its modest size relative to the cerebral cortex, is critically involved in the pathology and clinical manifestations of numerous neurodegenerative diseases (NDDs). Historically, research on NDDs such as Alzheimer disease, Lewy body disease, and frontotemporal lobar degeneration predominantly adopted a cortico-centric perspective. However, emerging neuropathologic evidence underscores the brainstem's essential role, with early pathologic changes often predating cortical involvement. This chapter highlights salient points regarding the pathology and clinicopathologic correlations of brainstem involvement across major NDDs, emphasizing the chronology of disease progression. Key mechanisms, including protein misfolding and aggregation, selective neuronal vulnerability, and neurotransmitter dysfunction, are explored. Clinical correlations illustrate how early brainstem pathology significantly contributes to prodromal symptoms and helps define distinct clinical phenotypes, such as autonomic dysfunction, sleep disturbances, and mood disorders. Recognizing the chronologic order and specific nuclei affected in the brainstem broadens our understanding of disease progression, highlighting opportunities for targeted interventions at earlier disease stages.

Keywords:  Brainstem; Clinicopathologic correlations; Neurodegenerative diseases; Neuropathology; Protein aggregation

DOI:  https://doi.org/10.1016/B978-0-443-15736-3.00017-2