bims-proned 2025-08-03 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–08–03
twenty-two papers selected by
Verena Kohler, Umeå University

Aβ42 promotes the aggregation of α-synuclein splice isoforms via heterogeneous nucleation.
Polyserine-tau interactions modulate tau fibrillization.
EXPRESS: Hydrophobic Hydration and Light Transport in α-Synuclein Protein Solutions in the Near-Infrared.
Differentiating α-synuclein aggregates using charge-sensitive gold nanoclusters.
Decoding the Relationship between Alzheimer's Disease and Type-2 Diabetes via the Protein Aggregation Prism.
Design of Zwitterionic Conjugated Polymers as Protein Aggregation Inhibitors.
Stoichiometric 14-3-3ζ binding promotes phospho-Tau microtubule dissociation and reduces aggregation and condensation.
Natural Bioactive Compounds as Modulators of Autophagy: A Herbal Approach to the Management of Neurodegenerative Diseases.
Kinetics of seeded protein aggregation: Theory and application.
Elevated ubiquitin phosphorylation by PINK1 contributes to proteasomal impairment and promotes neurodegeneration.
In Silico Investigation of Ganoderic Acid A Targeting Amyloid-Beta and Tau Protein Aggregation in Alzheimer's Disease.
Impact of α-synuclein fibril structure on seeding activity in experimental models of Parkinson's disease.
The role of endolysosomal progranulin and TMEM106B in neurodegenerative diseases.
Araloside A Induces Raf/MEK/ERK-Dependent Autophagy to Mitigate Alzheimer's and Parkinson's Pathology in Cellular and C. elegans Models.
Pathogenic TRIM74 Mutation Disrupts Protein Homeostasis and Triggers Proteotoxic Neurodegeneration via Structural Destabilization.
Nanoparticles with Ampholytic Surfaces for Binding and Disintegration of Amyloid Fibrils.
Strain-Distinct α-Synuclein and Tau Cross-Seeding Uncovered by Correlative Approach with Optical Photothermal Infrared Sub-Micron Imaging.
The role of autophagy in the pathogenesis and treatment of multiple sclerosis.
Molecular mechanisms of Lobeline-mediated inhibition of lysozyme amyloidogenesis: A synergistic approach using biophysical and cheminformatics techniques.
Nanoplasmonic Infrared Microarray Sensor Enabling Structural Protein Biomarker-Based Drug Screening for Neurodegenerative Diseases.
Characterization of conformation-specific antibodies TOMA-1 and TTCM-1 for recombinant tau monomer and amplified brain derived tau oligomer.
Computational Cross-Aggregation Study of Dengue Virus NS1, Capsid Anchor and 2k Peptides With Human Amylin, Aβ42 and α-Synuclein Peptides.

FEBS Lett. 2025 Jul 26.

Aβ42 promotes the aggregation of α-synuclein splice isoforms via heterogeneous nucleation.

Alexander Röntgen, Zenon Toprakcioglu, Michele Vendruscolo.

  Increasing evidence suggests that amyloid-β (Aβ) and α-synuclein (αSyn) co-aggregate in Alzheimer's disease (AD) and Parkinson's disease (PD), an in other neurodegenerative disorders. We investigated how Aβ42 - the predominant Aβ form in AD - co-aggregates with four αSyn splice isoforms (αSyn-140, αSyn-126, αSyn-112 and αSyn-98) implicated in PD, finding evidence of a two-step process. Aβ42 first aggregated into fibrillar assemblies, which then acted as potent nucleation surfaces for initiating the aggregation of αSyn isoforms. Furthermore, pre-formed Aβ42 seeds promoted αSyn aggregation more strongly than in situ Aβ42 aggregates. Our results reveal a unified Aβ-αSyn co-aggregation mechanism, where Aβ aggregation and αSyn splicing synergistically drive co-deposition. These findings could help develop therapeutic tools to target key steps in disease-related co-aggregation pathways. Impact statement By demonstrating that Aβ42 fibril seeds serve as potent heterogeneous nucleation surfaces for four common α-synuclein splice isoforms, this study mechanistically links protein aggregation in Alzheimer's and Parkinson's diseases. Kinetic analysis identifies early cross-seeding events, suggesting intervention points to delay mixed amyloid pathologies in neurodegeneration.

Keywords:  Alzheimer's disease; Parkinson's disease; amyloid formation; amyloid‐β; neurodegeneration; α‐Synuclein splice isoforms

DOI:  https://doi.org/10.1002/1873-3468.70118
J Biol Chem. 2025 Jul 25. pii: S0021-9258(25)02374-9. [Epub ahead of print] 110523

Polyserine-tau interactions modulate tau fibrillization.

James Pratt, Kathleen McCann, Jeff Kuo, Roy Parker.

  Tau aggregates are the defining feature of multiple neurodegenerative diseases and contribute to the pathology of disease. However, the molecules affecting tau aggregation in cells are unclear. We previously determined that polyserine-rich domain containing proteins enrich in tau aggregates, form assemblies that can serve as sites of tau aggregation, and exacerbate tau aggregation in cells and mice. Herein, we show that polyserine domains are sufficient to define assemblies as sites of tau aggregation, in part, through localization of tau seeds. Purified polyserine self-assembles and directly interacts with monomeric and fibrillar tau. Moreover, polyserine-tau assemblies recruit RNA, leading to faster rates of tau fibrillization in vitro. Using polyserine variants, we found that enrichment in tau aggregates and stimulation of tau aggregation are separable functions of polyserine domains, with polyserine self-assembly stimulating tau aggregation. Together, our results show that polyserine self-assembles and directly interacts with tau to form preferred sites of tau aggregation.

Keywords:  Protein aggregation; RNA-protein interaction; Recombinant protein expression; Serine; Stress granule; Tau protein (Tau)

DOI:  https://doi.org/10.1016/j.jbc.2025.110523
Appl Spectrosc. 2025 Jul 30. 37028251367004

EXPRESS: Hydrophobic Hydration and Light Transport in α-Synuclein Protein Solutions in the Near-Infrared.

Marco A Saraiva.

  Currently, there is increasing interest in identifying the mechanistic characteristics of the α-synuclein amyloid protein aggregation during its early stages. The initiation of amyloid protein incubation was investigated by applying the concepts of hydrophobic hydration in the early-formed protein aggregates and the light transport in the protein samples by using near-infrared light. These are unexplored concepts in amyloid protein aggregation research. Early-formed protein aggregates develop solvent-exposed hydrophobic residue segments, and intramolecular and intermolecular interactions can be identified by hydrophobic hydration, while consecutive intramolecular interactions can cancel this effect. In the light transport within protein samples, at low protein concentrations, the early-formed protein aggregates achieve stability, whereas at higher concentrations, such as those found in neuronal synapses (∼50 µM), the early-formed aggregates continue to develop.

Keywords:  NIR; hydrophobic hydration; near-infrared light; protein aggregation; α-Synuclein

DOI:  https://doi.org/10.1177/00037028251367004
Nanoscale. 2025 Jul 31.

Differentiating α-synuclein aggregates using charge-sensitive gold nanoclusters.

Harpreet Kaur, Arpit Tyagi, Ishani Sharma, Deepak Sharma, Sharmistha Sinha.

The accumulation of α-synuclein (α-syn) aggregates in the brain is associated with Parkinson's disease, making it a promising biomarker for understanding the disease's pathogenesis. Distinguishing between oligomeric forms of amyloidogenic proteins is crucial, as their toxicity depends on conformation. This study leverages surface charge differences to distinguish α-syn monomers from amyloids. We employed label-free gold nanoclusters (AuNCs) with distinct surface charges to differentiate between wild-type and mutant [A30P]-α-Syn based on their charge characteristics. Fluorescence spectroscopy and electrochemical measurements were performed to evaluate the sensitivity and interaction mechanisms. Our results show that Pro-AuNCs exhibit greater sensitivity towards monomeric forms of both wild-type and mutant α-Syn, while His-AuNCs are more sensitive to amyloid forms. Impedance spectroscopy shows a detection limit in the picomolar range (pM), which is twice as sensitive as fluorescence measurements. Cell culture studies further validate our in vitro findings, demonstrating the effective specificity of AuNCs for detecting different conformations of α-syn. Overall, our results indicate that this probe can successfully identify aggregated and monomeric forms of α-syn, suggesting its potential for developing sensors aimed at understanding the etiology of Parkinson's disease.

DOI: https://doi.org/10.1039/d5nr00887e
ACS Chem Neurosci. 2025 Jul 28.

Decoding the Relationship between Alzheimer's Disease and Type-2 Diabetes via the Protein Aggregation Prism.

Vaishnavi Tammara, Atanu Das.

  Alzheimer's disease (AD) and type-2 diabetes (T2D) are two fatal human diseases and have been linked to the aberrant aggregation of two distinct peptides, amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP), respectively. These two peptide aggregates, even with distal deposition sites (brain and pancreas), act as mutual beneficiaries. We here unveiled the crosstalk in a self-consistent fashion using atomistic simulations by comparing the kinetics and thermodynamics of self- and cross-aggregations of Aβ42 and hIAPP and their modulations by preformed fibrillar templates. Templates (specifically hIAPP) generally accelerate aggregation, alter the relative order of aggregation rates (cross-aggregation > Aβ self-aggregation > hIAPP self-aggregation for nontemplated and hIAPP self-aggregation > cross-aggregation > Aβ self-aggregation for templated), and flip the mutual impact (hIAPP aggravates Aβ aggregation in nontemplated and the reverse in templated). Higher instances of breaking larger aggregates and longer residence times of smaller aggregates decelerate aggregation, whereas interpeptide electrostatics (universal) and hydrogen bonds (templated) assist it. However, the equilibrium aggregability pattern contradicts kinetic rank-ordering, as Aβ displays a higher aggregability than hIAPP, templates increase aggregability for both peptides, and Aβ's self-aggregability supersedes cross-aggregability, which further surpasses hIAPP's self-aggregability. The equilibrium ensembles encompass polymorphic, nonfibrillar oligomers having substantially reduced α-helicity and slight β-propensity, with both parallel and antiparallel interpeptide orientations, primarily stabilized by electrostatics. A higher equilibrium aggregability means a greater helix-breaking capacity, a bias toward parallel orientation, and a lesser structural polymorphism. Water expulsion from peptide surroundings and distortion of water tetrahedrality prove that aggregation follows the liquid-liquid phase separation (LLPS) model.

Keywords:  amylin; amyloid-β; liquid−liquid phase separation; oligomer; self vs cross-aggregation; unseeded vs seeded aggregation

DOI:  https://doi.org/10.1021/acschemneuro.5c00357
Langmuir. 2025 Jul 28.

Design of Zwitterionic Conjugated Polymers as Protein Aggregation Inhibitors.

Robin Rajan, Maninder Singh, Koyuru Suzuki, Kazuaki Matsumura.

Protein aggregation and misfolding is the root cause of several neurodegenerative diseases, including Alzheimer's disease, and can be mitigated using small molecules, peptides, and conjugated or zwitterionic polymers. However, polymers that are both conjugated and zwitterionic have not been evaluated as protein aggregation/misfolding inhibitors. Herein, to bridge this gap, we prepare polymers with a conjugated backbone bearing zwitterionic sulfobetaine moieties and poly(ethylene glycol) chains and examine their abilities to inhibit protein aggregation. These polymers not only strongly inhibit the aggregation of amyloid β peptide (Aβ42) and other proteins but also actively disrupt and solubilize pre-established amyloid fibrils. This dual functionality enables almost complete fibril disaggregation at concentrations lower than those required for existing alternatives and results in protective capability extension across a broad spectrum of proteins. The results open new avenues for advancing neurodegenerative disease treatment strategies and represent considerable progress in the development of biomedical materials.

DOI: https://doi.org/10.1021/acs.langmuir.5c02043
Commun Biol. 2025 Jul 31. 8(1): 1139

Stoichiometric 14-3-3ζ binding promotes phospho-Tau microtubule dissociation and reduces aggregation and condensation.

Janine Hochmair, Maxime C M van den Oetelaar, Leandre Ravatt, Lisa Diez, Lenne J M Lemmens, Renata Ponce-Lina, Rithika Sankar, Maximilian Franck, Gesa Nolte, Ekaterina Semenova, Satabdee Mohapatra, Christian Ottmann, Luc Brunsveld, Susanne Wegmann.

The microtubule (MT) association of protein Tau is decreased upon phosphorylation. Increased levels of phosphorylated Tau in the cytosol pose the risk of pathological aggregation, as observed in neurodegenerative diseases. We show that binding of 14-3-3ζ enhances cytosolic Tau solubility by promoting phosphorylated Tau removal from MTs, while simultaneously inhibiting Tau aggregation both directly and indirectly via suppression of condensate formation. These 14-3-3ζ activities depend on site-specific binding of 14-3-3 to Tau phosphorylated at S214 and S324. At sub-stoichiometric 14-3-3ζ concentrations, or in the presence of other 14-3-3ζ binding partners, multivalent electrostatic interactions promote Tau:14-3-3ζ co-condensation, offering a phosphorylation-independent mode of Tau-14-3-3ζ interactions. Given the high abundance of 14-3-3 proteins in the brain, 14-3-3 binding could provide efficient multi-modal chaperoning activity for Tau in the healthy brain and be important for preventing Tau aggregation in disease.

DOI: https://doi.org/10.1038/s42003-025-08548-0
Eur J Pharmacol. 2025 Jul 29. pii: S0014-2999(25)00757-5. [Epub ahead of print] 178003

Natural Bioactive Compounds as Modulators of Autophagy: A Herbal Approach to the Management of Neurodegenerative Diseases.

Vinod Kumar Nelson, M Yasmin Begum, Punna Rao Suryadevara, Sudha Divya Madhuri Kallam, Siva Parsad Panda, Anoop Bodapati, Vaishnavi Sanga, Ashok Kumar Bishoyi, Suhas Ballal, Mekha Monsi, Chakshu Walia, G V Siva Prasad, Mosleh Mohammad Abomughaid, Sandeep Shukla, Payal Chauhan, Niraj Kumar Jha.

  Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Polyglutamine (polyQ), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) disease are a significant health concern that affects millions of people every year worldwide. The main pathological hallmark of various NDs is the formation of misfolded protein aggregation and accumulation of inclusion bodies. These protein aggregates are mainly responsible for producing toxic effects and initiating neuronal cell death, ultimately promoting various NDs. On the other hand, the patients suffering from these kinds of diseases live in impaired conditions, imposing a substantial financial burden on the family. However, the current treatment strategies can only offer temporary relief from the disease symptoms and can't reverse the disease completely. Hence, there is an urgent need for specific and novel drug treatment that can significantly eradicate NDs. Ubiquitin proteasome system (UPS) and autophagy are the two essential intracellular defensive mechanisms that are involved in clearing the protein aggregates, pathogens, and damaged organelles from the cytoplasm and maintaining protein homeostasis. Nevertheless, UPS is inefficient in removing some kinds of organelles and aggregating-prone proteins, specifically in neuronal and glial cells. Under this kind of circumstance, the autophagy mechanism plays a vital role in eliminating the accumulated protein aggregates and other toxic elements from the cytoplasm of the neuronal cells that initiate oxidative stress. However, in NDs, the autophagy function is impaired, and the protein aggregates can't be eliminated effectively. Hence, forced up-regulation of autophagy function by applying various external agents could be a potential therapeutic strategy to control NDs like AD, PD, HD, and ALS. In this review, we focused on different kinds of plant-derived compounds that induce autophagy. We also discussed the role of these plant-derived autophagy modulators in various NDs. In this way, the current review will be a standalone reference to the researchers working in this area.

Keywords:  Autophagy; Natural products; Neurodegeneration; Signaling; Therapeutics

DOI:  https://doi.org/10.1016/j.ejphar.2025.178003
J Chem Phys. 2025 Jul 28. pii: 045101. [Epub ahead of print]163(4):

Kinetics of seeded protein aggregation: Theory and application.

Alexander J Dear, Georg Meisl, Jing Hu, Tuomas P J Knowles, Sara Linse.

"Seeding" is the addition of preformed fibrils to a solution of monomeric protein to accelerate its aggregation into new fibrils. It is a versatile and widely used tool for scientists studying protein aggregation kinetics, as it enables the isolation and separate study of discrete reaction steps contributing to protein aggregation, specifically elongation and secondary nucleation. However, the seeding levels required to achieve dominating effects on each of these steps separately have been established largely by trial-and-error due in part to the lack of availability of integrated rate laws valid for moderate to high seeding levels and generally applicable to all common underlying reaction mechanisms. Here, we improve on a recently developed mathematical method based on Lie symmetries for solving differential equations and with it derive such an integrated rate law. We subsequently develop simple expressions for the amounts of seed required to isolate each step. We rationalize the empirical observation that fibril seeds must often be broken up into small pieces to successfully isolate elongation. We also derive expressions for average fibril lengths at different times in the aggregation reaction and explore different methods to break up fibrils. This paper will provide an invaluable reference for future experimental and theoretical studies in which seeding techniques are employed and should enable more sophisticated analyses than have been performed to date.

DOI: https://doi.org/10.1063/5.0273677
Elife. 2025 Jul 31. pii: RP103945. [Epub ahead of print]14

Elevated ubiquitin phosphorylation by PINK1 contributes to proteasomal impairment and promotes neurodegeneration.

Cong Chen, Tong-Yao Gao, Hua-Wei Yi, Yi Zhang, Tong Wang, Zhi-Ling Lou, Tao-Feng Wei, Yun-Bi Lu, Tingting Li, Chun Tang, Wei-Ping Zhang.

  Ubiquitin (Ub), a central regulator of protein turnover, can be phosphorylated by PINK1 (PTEN-induced putative kinase 1) to generate S65-phosphorylated ubiquitin (pUb). Elevated pUb levels have been observed in aged human brains and in Parkinson's disease, but the mechanistic link between pUb elevation and neurodegeneration remains unclear. Here, we demonstrate that pUb elevation is a common feature under neurodegenerative conditions, including Alzheimer's disease, aging, and ischemic injury. We show that impaired proteasomal activity leads to the accumulation of sPINK1, the cytosolic form of PINK1 that is normally proteasome-degraded rapidly. This accumulation increases ubiquitin phosphorylation, which then inhibits ubiquitin-dependent proteasomal activity by interfering with both ubiquitin chain elongation and proteasome-substrate interactions. Specific expression of sPINK1 in mouse hippocampal neurons induced progressive pUb accumulation, accompanied by protein aggregation, proteostasis disruption, neuronal injury, neuroinflammation, and cognitive decline. Conversely, Pink1 knockout mitigated protein aggregation in both mouse brains and HEK293 cells. Furthermore, the detrimental effects of sPINK1 could be counteracted by co-expressing Ub/S65A phospho-null mutant but exacerbated by over-expressing Ub/S65E phospho-mimic mutant. Together, these findings reveal that pUb elevation, triggered by reduced proteasomal activity, inhibits proteasomal activity and forms a feedforward loop that drives progressive neurodegeneration.

Keywords:  PINK1; biochemistry; chemical biology; mouse; neurodegeneration; phosphorylation; proteasome; ubiquitin

DOI:  https://doi.org/10.7554/eLife.103945
Int J Med Mushrooms. 2025 ;27(9): 85-92

In Silico Investigation of Ganoderic Acid A Targeting Amyloid-Beta and Tau Protein Aggregation in Alzheimer's Disease.

Abuzer Ali, Ankit Ganeshpurkar, Aditya Ganeshpurkar, Nazneen Dubey.

Alzheimer's disease (AD) represents a significant challenge in neurodegenerative disorders, characterized by the accumulation of amyloid-beta (Aβ) plaques and tau protein tangles in the brain. Current treatments provide symptomatic relief but do not halt disease progression. ganoderic acid A, derived from Ganoderma lucidum, has shown to act as a dual inhibitor of Aβ and tau protein aggregation through in vitro and animal model studies. This study aims to explore the therapeutic potential of ganoderic acid A using in silico methods to predict its binding affinity and mode of interaction with Aβ and tau proteins. Analysis included molecular docking simulations using computational models to evaluate the binding of ganoderic acid A to Aβ and tau proteins. Various tools were employed to predict the binding energy, interaction sites (Autodock), and MD (CABSflex 2.0) of these complexes. Ganoderic acid A demonstrated favorable binding energies and interactions with both Aβ and tau proteins. The compound exhibited potential dual inhibition capabilities by forming stable complexes with critical residues involved in Aβ aggregation and tau protein hyperphosphorylation. The findings suggest that ganoderic acid A holds promise as a dual inhibitor of Aβ and tau protein aggregation in AD. By targeting these key pathological processes, ganoderic acid A may offer therapeutic benefits in halting or slowing disease progression. Confirming these predictions and advancing ganoderic acid A as a possible AD treatment will require additional experimental validation, including in vitro and in vivo research.

DOI: https://doi.org/10.1615/IntJMedMushrooms.2025059137
NPJ Parkinsons Dis. 2025 Jul 31. 11(1): 224

Impact of α-synuclein fibril structure on seeding activity in experimental models of Parkinson's disease.

Junichiro Ohira, Masanori Sawamura, Kenichi Kawano, Risa Sato, Tomoyuki Taguchi, Tomoyuki Ishimoto, Jun Ueda, Masashi Ikuno, Shu-Ichi Matsuzawa, Katsumi Matsuzaki, Ryosuke Takahashi, Hodaka Yamakado.

The central pathogenesis of Parkinson's disease involves the misfolding and aggregation of α-synuclein (α-syn). There is a widespread belief that α-syn can propagate in a prion-like manner, and α-syn preformed fibrils (PFFs) have been widely used to establish α-syn propagation models. However, achieving standardized protocols for generating PFFs is challenging due to the influence of various factors on propagation efficiency, resulting in inter-laboratory and inter-experimental variability. Among these factors, the size of the PFFs is considered the most influential as unsonicated PFFs exhibit limited seeding and propagation abilities. Therefore, the objective of our research is to examine the impact of the size and conformation of sonicated PFFs on seeding activity. PFFs were sonicated under various conditions using a conventional water bath sonicator and a high-power sonicator, which is commonly used for DNA shearing in next-generation sequencing. Each sonicated PFF was analyzed for in vitro/in vivo seeding activities, after size confirmation by electron microscopy and a conformational analysis by Fourier Transform Infrared (FTIR) spectroscopy. Strong sonication for 30 min generated extremely short fibrils with the highest seeding activity, which is the optimal condition for the propagation model, whereas sonication for 60 minutes or more led to a reduction in seeding activity. FTIR spectroscopy suggested that sonication disrupted the aggregated strands and generated new fibril ends, thereby accounting for the increased seeding activity; however, prolonged sonication for 60 min or more released monomers with disrupted β-sheet structure from PFFs and reduced the seeding activity. In conclusion, the balance between size reduction and preservation of the β-sheet structure in PFFs plays a critical role in seeding activity. Optimizing these parameters of α-syn PFFs can help improve reproducible preclinical animal models based on α-syn propagation.

DOI: https://doi.org/10.1038/s41531-025-01080-2
Mol Neurodegener. 2025 Jul 26. 20(1): 86

The role of endolysosomal progranulin and TMEM106B in neurodegenerative diseases.

Hideyuki Takahashi, Stephen M Strittmatter.

  Although different neurodegenerative diseases are defined by distinct pathological proteins, they share many common features including protein aggregation. Despite this commonality, most current therapeutic approaches in the field, such as anti-aggregate antibodies, are focused on individual diseases or single neuropathologies with only limited success. The endolysosomal proteins progranulin and TMEM106B were both initially associated with frontotemporal lobar degeneration but have subsequently also been linked to other neurodegenerative diseases. Thus, these proteins are predicted to participate in common pathogenic pathways shared across various neurodegenerative diseases. Importantly, recent discoveries of TMEM106B amyloid fibrils in varied neurodegenerative diseases and glycosphingolipid regulation by progranulin and TMEM106B further support their central roles in cross-disease neurodegenerative mechanisms. This review summarizes recent advances in progranulin and TMEM106B function within the endolysosomal system and neurodegenerative diseases. It describes preclinical models and therapeutic approaches for progranulin- and TMEM106B-associated diseases. We also discuss future direction leading to novel alternative therapies targeting shared mechanisms in neurodegenerative diseases.

Keywords:  Aging; Alzheimer’s disease; Amyloid fibrils; Endolysosome; Frontotemporal Lobar degeneration; GBA1; Glycosphingolipid; Parkinson’s disease; Progranulin; TMEM106B

DOI:  https://doi.org/10.1186/s13024-025-00873-6
Mol Neurobiol. 2025 Jul 31.

Araloside A Induces Raf/MEK/ERK-Dependent Autophagy to Mitigate Alzheimer's and Parkinson's Pathology in Cellular and C. elegans Models.

Xue Chen, Xing-Yue Zhou, Cai Lan, Hai-Jun Fu, Zhi-Chao Li, Meng-Yi Chen, Yong-Ping Wen, Lu Yu, Da-Lian Qin, An-Guo Wu, Jian-Ming Wu, Xiao-Gang Zhou.

  Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by pathological protein aggregation and oxidative stress, leading to progressive neurodegeneration. Enhancing autophagy, the primary intracellular pathway for clearing misfolded proteins, represents a promising therapeutic strategy. In this study, we identify Araloside A (ARA), a triterpenoid saponin derived from Aralia elata, as a potent autophagy inducer that alleviates AD- and PD-related pathology. In neuronal cell models, ARA promotes autophagosome formation, increases LC3-II and Beclin-1 levels, and decreases P62, indicating enhanced autophagic activity. Mechanistic investigations reveal that ARA directly binds to Raf, MEK, and ERK proteins and activates autophagy in a Raf/MEK/ERK-dependent manner. This activation facilitates the clearance of APP, total Tau, phosphorylated Tau, and α-synuclein, thereby reducing cytotoxicity. Furthermore, in transgenic Caenorhabditis elegans models of AD and PD, ARA treatment alleviates protein aggregation and behavioral deficits via ERK-dependent autophagy. Together, these findings identify ARA as a natural compound that enhances autophagic clearance of neurotoxic aggregates via Raf/MEK/ERK pathway activation, offering promising therapeutic insights for neurodegenerative proteinopathies.

Keywords:  Alzheimer’s disease; Araloside A; Autophagy; Parkinson’s disease; Pathological proteins; Raf/MEK/ERK

DOI:  https://doi.org/10.1007/s12035-025-05242-4
ACS Chem Neurosci. 2025 Jul 30.

Pathogenic TRIM74 Mutation Disrupts Protein Homeostasis and Triggers Proteotoxic Neurodegeneration via Structural Destabilization.

S Rehan Ahmad, Abdullah M AlShahrani, Anupriya Kumari.

  Ubiquitin ligases play a critical role in maintaining proteostasis, synaptic function, and neuronal survival, and their dysfunction is increasingly implicated in neurodevelopmental disorders with neurodegenerative features. In this study, we investigate mutation in the ubiquitin ligase gene TRIM74 [a novel homozygous missense variant c.562C > T (p.Pro121Leu)] in a 5-year-old male proband presenting with global developmental delay, hypotonia, seizures, and diffuse cerebral atrophy with mega cisterna magna. Structural and simulation studies revealed that Pro121, located at the start of a β sheet, likely functions as a sheet breaker. Substitution to leucine (P121L) resulted in aberrant beta strand extension, protein destabilization, and increased aggregation propensity. Free energy calculations indicated that all possible substitutions at this position were destabilizing. Multiple in silico prediction tools consistently classified the mutation as damaging or disease-causing. In proband-derived fibroblasts, TRIM74-P121L exhibited significant cytosolic aggregation and elevated Proteostat-positive granules, reflecting proteotoxic stress. Despite comparable transcript and total protein levels, mutant cells showed increased cell death and impaired cell cycle progression. Interaction network and gene ontology analyses revealed that TRIM74 and its partners are involved in ubiquitination, protein quality control, and transcriptional regulation─processes essential to neuronal homeostasis. TRIM74 expression was highest in the cerebellum and medulla, aligning with MRI abnormalities. Together, our findings establish the aberrant functioning of mutant TRIM74 as a pathogenic cause of neurodegenerative neurodevelopmental disorder and highlight the importance of ubiquitin ligases in maintaining neuronal integrity and preventing neurodegeneration.

Keywords:  TRIM74; neurodevelopmental disorder; protein aggregation; proteostasis dysfunction; ubiquitin ligase

DOI:  https://doi.org/10.1021/acschemneuro.5c00458
ACS Cent Sci. 2025 Jul 23. 11(7): 1218-1229

Nanoparticles with Ampholytic Surfaces for Binding and Disintegration of Amyloid Fibrils.

Suman Mandal, Minh Dang Nguyen, Nikhil Ranjan Jana, T Randall Lee.

Amyloid fibrils and associated protein aggregates are key contributors to a range of neurodegenerative diseases. Recent studies suggest that nanoparticles with tailored surface chemistries can effectively bind to and disrupt these fibrils. Here, we investigate the role of nanoparticle surface charge in mediating interactions with amyloid fibrils and promoting their disintegration. We synthesized seven types of charged iron oxide nanoparticles (cationic, anionic, and ampholytic) in colloidal form with hydrodynamic diameters ranging from 15 to 40 nm. Interaction studies with mature lysozyme fibrils revealed that ampholytic nanoparticles exhibited the highest binding affinity among the tested surface types. This enhanced affinity is attributed to reduced nonspecific interactions and favorable electrostatic compatibility. Ampholytic nanoparticles disrupted mature amyloid fibrils approximately 2.5 times more effectively than other surface-charged nanoparticles, leading to smaller fibril fragments via mechanical agitation. We further show that agitation-induced mechanical force, along with piezocatalytically generated reactive oxygen species (ROS), contributes to fibril degradation. These findings highlight the critical role of ampholytic surface charge in promoting fibril disintegration and suggest that such nanoparticles could be leveraged in therapeutic strategies for neurodegenerative diseases involving amyloid aggregation.

DOI: https://doi.org/10.1021/acscentsci.5c00519
J Am Chem Soc. 2025 Jul 28.

Strain-Distinct α-Synuclein and Tau Cross-Seeding Uncovered by Correlative Approach with Optical Photothermal Infrared Sub-Micron Imaging.

Xiaoni Zhan, Wen Li, Eric Hatterer, Jean-Philippe Courade, Kristin Piché, Oxana Klementieva, Jia-Yi Li.

The co-occurrence of α-synuclein (αSyn) and Tau in synucleinopathies and tauopathies suggests a complex interplay between these proteins. Their cross-seeding enhances fibrillization, leading to the formation of diverse amyloid-specific structures enriched with β-sheets, which may influence their biological functions. However, existing tools cannot differentiate structural polymorphs directly in cells, as conventional microscopic approaches have limitations in providing structural insights into aggregates. As a result, a structurally relevant characterization of amyloids in their native cellular environment has not yet been achieved. In this study, we characterize the structural rearrangements of newly formed αSyn inclusions cross-seeded by different αSyn and Tau preformed fibrils (PFFs) directly in cells, using a correlative approach that combines submicron optical photothermal infrared (O-PTIR) microspectroscopy and confocal microscopy. We found that hybrid PFFs synthesized from αSyn, and two Tau isoforms (Tau3R and Tau4R) exhibit variations in αSyn and Tau composition. Specifically, structural polymorphs composed of αSyn and Tau3R exhibit the highest β-sheet content and most potent seeding potency, leading to enhanced phosphorylation within cellular inclusions. Importantly, we demonstrate that cellular inclusions inherit structural motifs from their donor seeds and exhibit distinct spatial and structural evolution. By providing subcellular-resolution structural imaging of amyloid proteins, our study uncovers divergent mechanisms of αSyn aggregation induced by αSyn/Tau PFFs in both mixed and hybrid formats.

DOI: https://doi.org/10.1021/jacs.5c02811
Autophagy Rep. 2025 ;4(1): 2529196

The role of autophagy in the pathogenesis and treatment of multiple sclerosis.

Giulio Righes, Luana Semenzato, Konstantinos Koutsikos, Veronica Zanato, Paolo Pinton, Carlotta Giorgi, Simone Patergnani.

  Autophagy is a crucial cellular process responsible for the degradation and recycling of damaged or unnecessary components, maintaining cellular homeostasis and protecting against stress. Dysregulation of autophagy has been implicated in a variety of neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Various types of autophagy exist, each with distinct mechanisms, such as macroautophagy, mitophagy, lipophagy, and chaperone-mediated autophagy. These processes are essential for the removal of toxic substrates like protein aggregates and dysfunctional mitochondria, which are vital for neuronal health. In neurodegenerative diseases, the impairment of these clearance mechanisms leads to the accumulation of harmful substances, which accelerate disease progression. Modulating autophagy has emerged as a promising therapeutic strategy, with ongoing studies investigating molecules that can either stimulate or regulate this process. However, despite its potential, significant challenges remain in translating preclinical findings into clinically effective treatments. In this review, we will explore the different types of autophagy, their roles in neurodegenerative diseases, and the therapeutic potential associated with modulating these processes.

Keywords:  Multiple sclerosis; autophagy; ferritinophagy; lipophagy; mielinophagy; mitophagy; therapy

DOI:  https://doi.org/10.1080/27694127.2025.2529196
Biophys Chem. 2025 Jul 24. pii: S0301-4622(25)00114-0. [Epub ahead of print]326 107502

Molecular mechanisms of Lobeline-mediated inhibition of lysozyme amyloidogenesis: A synergistic approach using biophysical and cheminformatics techniques.

Vibeizonuo Rupreo, Ria Saha, Jhimli Bhattacharyya, Rajib Kumar Mitra.

  Numerous pathological conditions, collectively termed amyloidosis, are associated with the aggregation of misfolded proteins under stressed physiochemical conditions. Natural compounds capable of modulating protein aggregation or disassembling preformed fibrils hold promise as potential therapeutic candidates for treating aggregation-related diseases. In this study, we aim to examine the binding interaction and effectiveness of Lobeline (Lob), a piperidine alkaloid, in preventing the formation of acid-denatured Lysozyme (Lyz) amyloid using various spectroscopic, cheminformatics and imaging techniques. Steady-state and time-resolved fluorescence measurements confirm a direct interaction between Lyz and Lob with a binding constant of ∼106 M-1 with a 1:1 binding stoichiometry. The association has been found to be spontaneous and is driven by entropy involving non-electrostatic interactions. Molecular Docking shows that Lob stabilizes Lyz by hydrophobic and hydrophilic interactions. The anti-amyloid properties of Lob in Lyz amyloid fibrils are assessed through a range of in vitro techniques, including turbidity measurement, dynamic light scattering (DLS), Thioflavin T (ThT) fluorescence, Circular Dichroism studies and Field Emission Scanning Electron Microscopy (FESEM) imaging. These studies demonstrate that Lob halts the fibrillation of acid-treated Lyz at the nucleation stage by providing alternative pathways for hydrogen bonding and other weak interactions with key amino acid residues necessary for the formation of oligomers and fibrils.

Keywords:  Antiamyloid activity; Lobeline; Lysozyme fibrillation; Structure-function relationship

DOI:  https://doi.org/10.1016/j.bpc.2025.107502
Adv Sci (Weinh). 2025 Jul 28. e00320

Nanoplasmonic Infrared Microarray Sensor Enabling Structural Protein Biomarker-Based Drug Screening for Neurodegenerative Diseases.

Deepthy Kavungal, Enzo Morro, Senthil T Kumar, Berkay Dagli, Hilal A Lashuel, Hatice Altug.

  The misfolding of proteins from native monomers into β-sheet-rich fibrils via oligomers is a key hallmark of neurodegenerative diseases (NDDs). Identifying and screening drugs that inhibit protein aggregation for early disease intervention remains challenging due to the limitations of existing methods. This work introduces a novel nanoplasmonic infrared microarray sensor for label-free and high-throughput drug screening based on structural protein biomarkers in NDDs. The sensor employs 2D arrays of nanoplasmonic units compartmentalized in micropatterned polymeric microwells for high-throughput protein sensing and secondary structural analysis. The flexibility of the on-chip integrated microarray sensor is showcased through ultra-compact 48, 96, and 384 microwell designs, enabling detection from as low as 2 nL of sample volume and with a 100 pg/mL sensitivity in under a minute of in situ measurement. The drug screening capability is validated by assessing multiple drug compounds in a multiplexed manner for their inhibiting effect on aSyn aggregation, an important NDDs protein biomarker. The microarray sensor successfully quantified the secondary structural changes in drug-treated protein samples, detecting both oligomers and fibrils, which the conventional fluorescence-based assays failed to do. Thus, the nanoplasmonic microarray sensor is a promising advancement in the NDDs and pharmaceutical research for drug screening.

Keywords:  alpha‐synuclein; high‐throughput screening; infrared spectroscopy; metasurfaces; microarray; neurodegenerative diseases; plasmonics

DOI:  https://doi.org/10.1002/advs.202500320
Biochim Biophys Acta Mol Basis Dis. 2025 Jul 28. pii: S0925-4439(25)00343-6. [Epub ahead of print]1871(8): 167995

Characterization of conformation-specific antibodies TOMA-1 and TTCM-1 for recombinant tau monomer and amplified brain derived tau oligomer.

Md Anzarul Haque, Mauro Montalbano, Sheeza Khan, Nicha Puangmalai, Nemil Bhatt, Nikita Shchankin, Cynthia Jerez, Rakez Kayed.

  Tauopathies are a set of neurodegenerative diseases characterized by the pathological accumulation of aggregated tau in the brain. Recent breakthrough evidence has revealed the existence of different strains of tau oligomer (TauO) which direct the different pathological presentation of individual tauopathies. Extensive research efforts have been devoted to search for specific antibodies or drug candidates which target TauO to serve as promising alternatives to treat Alzheimer's disease (AD) in future. To screen for the antibodies which are able to bind with amplified brain derived tau oligomer (aBDTO), we have investigated the binding parameters of the tau oligomer-specific monoclonal antibody-1 (TOMA-1) and toxic tau conformation-specific monoclonal antibody-1 (TTCM-1) with the recombinant tau monomer (rTauM) and aBDTO using isothermal titration calorimetry (ITC). TOMA-1 specifically recognizes the amino acid sequences 367-386, 382-401 and 367-386 and TTCM-1 specifically recognizes the amino acid sequence 307-326 of rTauM and aBDTO, respectively. Our results demonstrated that both TOMA-1 and TTCM-1 have a high binding affinity with aBDTO compared to rTauM. We also observed that higher the binding affinity of the antibody to the aBDTO, lower was the toxicity of the aBDTO and vice versa. Our study taken together presents both TOMA-1 and TTCM-1 to be potential immunotherapeutic agents against AD.

Keywords:  Amplified brain derived tau oligomer; Conformation-specific antibodies; Cytotoxicity; H-tau expressing primary cortical neurons; Isothermal titration calorimetry; Recombinant tau monomer

DOI:  https://doi.org/10.1016/j.bbadis.2025.167995
J Mol Recognit. 2025 Sep;38(5): e70009

Computational Cross-Aggregation Study of Dengue Virus NS1, Capsid Anchor and 2k Peptides With Human Amylin, Aβ42 and α-Synuclein Peptides.

Dwaipayan Chaudhuri, Satyabrata Majumder, Kalyan Giri.

  Dengue virus, an arbovirus, is the causal factor of thousands of deaths around the globe, although the long-term consequences of the same have not been elucidated in great detail. The virus encodes for a polyprotein, which is later cleaved to form multiple proteins, of which NS1 protein oligomerization domain, 2k, and capsid anchor are three aggregation-prone peptides, as have been previously seen. A relatively under-studied angle of these peptides is the role of these peptides in cross-aggregation with certain human aggregation-prone proteins. Here, we have tried to shed light on this cross-aggregation perspective of these three peptides in combination with human amylin, α-synuclein, and Aβ42 peptides, making use of extensive all-atom MD simulations to study the cross-aggregation behavior of the peptides in atomistic detail. The intricacies of peptide aggregation have been studied based on the aggregate size calculation and the solvent accessible surface area method, giving a direct estimate of the aggregation seed development process. The importance of the different peptide residues in both self and cross-aggregation has been elucidated. This study may shed light on the cross-aggregation potential of these three peptides and help to explain the viral pathogenesis pathway in greater detail.

Keywords:  aggregate size analysis; dengue virus 2k peptides; dengue virus NS1; dengue virus capsid anchor; dengue virus peptide cross‐aggregation; inter‐peptide contact frequency

DOI:  https://doi.org/10.1002/jmr.70009