bims-proned 2025-08-10 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–08–10
24 papers selected by
Verena Kohler, Umeå University

Isobavachalcone inhibits α-synuclein fibrillogenesis and its Parkinson's disease variants, disassembles the mature fibrils and alleviates cellular toxicity.
Small Molecule Modulators of α-Synuclein Phase Separation.
Phytocompounds as modulators of HSF1 in neurodegenerative disease: Special emphasis on Alzheimer's disease.
Impairment of neuronal activity occurs at the early stages of the aggregation cascade of Aβ 1-42 and mutant Tau.
Modulation of biomolecular aggregate morphology and condensate infectivity.
Alpha-Synuclein Dysregulation in Systemic Pathophysiology of Synucleinopathies.
Cytoplasmic TDP-43 leads to early functional impairments without neurodegeneration in a Serotonergic Neuron-Specific C. elegans Model.
Aggregation of TDP-43307-319: A Dual Pathway to Forming Cylindrins and Fibrils and a Contribution to the Etiology of Amyotrophic Lateral Sclerosis.
mGluR4-Npdc1 complex mediates α-synuclein fibril-induced neurodegeneration.
Berberine mitigates neurotoxicity of misfolded protein oligomers by interacting with the cell membrane and subsequent internalization, without altering their structure.
A Bioinformatic Analysis of BAG Protein Interactors and Pathways in Alzheimer's and Parkinson's Disease.
Monomeric α-Synuclein Real-Time Induced Conversion: A New Approach to the Diagnostics of Neurodegenerative Synucleinopathies with Weak RT-QuIC Responses.
NMDA receptors in neurodegenerative diseases: mechanisms and emerging therapeutic strategies.
α-Synuclein Drives SNARE-Dependent Tubular Remodeling of Vesicles.
Regulation of polyamine interconversion enzymes affects α-Synuclein levels and toxicity in a Drosophila model of Parkinson's Disease.
Elevated plasma levels of alpha-synuclein are dispensable for Parkinson's disease pathology.
Phosphorylated α-synuclein in CSF and plasma does not reflect synucleinopathy.
The role of hydrophobic collapse in cytotoxic and functional amyloid oligomerization.
Aggregation potency and proinflammatory effects of SARS-CoV-2 proteins.
Structural analyses define the molecular basis of clusterin chaperone function.
Lipid packing defects are necessary and sufficient for membrane binding of α-synuclein.
Deuterium trafficking, mitochondrial dysfunction, copper homeostasis, and neurodegenerative disease.
Diabetic retinopathy and Alzheimer's disease: Convergence of the unfolded protein response in neurodegeneration.
Hypoxia ameliorates neurodegeneration and movement disorder in a mouse model of Parkinson's disease.

Int J Biol Macromol. 2025 Aug 03. pii: S0141-8130(25)07098-9. [Epub ahead of print] 146541

Isobavachalcone inhibits α-synuclein fibrillogenesis and its Parkinson's disease variants, disassembles the mature fibrils and alleviates cellular toxicity.

Feiling Xie, Cheng Zhu, Lingling Sun, Qimeng Lin, Peiyi Fang, Ao Li, Tianqi Lai, Conghui Ma, Yu Zhang, Yinghong Lu, Yanshan Chen, Yan Zhang, Shifeng Xiao, Xuesong Yang, Guowei Yin, Guohua Lv.

  The accumulation of α-Synuclein (α-Syn) aggregates into neuronal inclusions is a hallmark of Parkinson's disease (PD), making α-Syn a key target for PD therapeutics. Here, we demonstrate that the chalcone compound isobavachalcone (IBC) inhibits α-Syn aggregation and remodels mature fibrils into fragmented filaments. IBC exhibits dose-dependent inhibition of wild-type α-Syn and PD-linked mutants (E46K, H50Q, G51D, and A53T) while effectively abrogating seeded fibrillization. Biophysical characterization using circular dichroism (CD), transmission electron microscopy (TEM), dynamic light scattering (DLS), and nuclear magnetic resonance (NMR) revealed that IBC prevents the formation of β-sheet-enriched α-Syn aggregates. In silico docking suggests that IBC binds to the protofilament interface, blocking aggregation. Additionally, IBC disassembles α-Syn fibrils into fragmented filaments and mitigates α-Syn-induced cytotoxicity in CCK-8 cell viability assays. Our findings establish IBC as a chalcone-based molecule capable of binding α-Syn and remodeling its fibrillogenesis, providing a potential molecular template for developing PD inhibitors targeting α-Syn aggregation.

Keywords:  Amyloidosis inhibitors; Isobavachalcone; Parkinson's disease; Protein aggregation; α-Synuclein

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.146541
ACS Chem Neurosci. 2025 Aug 06.

Small Molecule Modulators of α-Synuclein Phase Separation.

Debabrata Sarkar, Sumangal Roychowdhury, Rajeev Jain, Krishnananda Chattopadhyay, Biswadip Banerji.

  Parkinson's disease (PD) is a progressive neurodegenerative condition that affects the brain's ability to control movement. The disease occurs when nerve cells of the brain become impaired. Alpha-synuclein protein (α-Syn) aggregation followed by fibrillation is a hallmark of PD. Recent studies showed that the liquid-liquid phase separation (LLPS) and droplet formation of α-Syn protein play a crucial role in the pathology of PD. We synthesized novel zwitterionic compounds (3), which inhibited α-Syn phase separation and subsequent formation of fibrillary aggregates in a concentration-dependent manner.

Keywords:  Parkinson’s disease; alpha-synuclein; liquid−liquid phase separation; neuro-degenerative disorders; protein aggregation; small molecule inhibitors

DOI:  https://doi.org/10.1021/acschemneuro.5c00302
Eur J Pharmacol. 2025 Aug 05. pii: S0014-2999(25)00788-5. [Epub ahead of print]1005 178034

Phytocompounds as modulators of HSF1 in neurodegenerative disease: Special emphasis on Alzheimer's disease.

Vinod Kumar Nelson, M Yasmin Begum, Ayed A Dera, Syed Parween Ali, Punna Rao Suryadevara.

  Alzheimer's disease (AD) is the most common age-related neurodegenerative disease that affects millions of people every year globally. In addition to a drastic rise in AD cases, there is a significant increase in the death rate as well. According to the latest statistics, the death rate increased to 1.62 million in 2019 and is expected to rise further. The primary pathological hallmark of the disease is the accumulation of misfolded aggregates, such as amyloid beta (Aβ) plaques and tau neurofibrillary tangles, which induce toxic effects and initiate neuronal dysfunction, ultimately leading to disease symptoms, including cognitive impairment. Hence, targeting and eliminating these protein aggregates could significantly inhibit the disease pathogenesis. Previous studies have also suggested that the activation of heat shock factor 1 (HSF1) and the up-regulation of its encoded heat shock proteins (HSPs) can clear toxic aggregates by triggering proteostasis mechanisms, such as autophagy and the ubiquitin-proteasome system (UPS). However, in neurodegenerative diseases (NDs) like AD, the proteotoxic stress response (PSR) is defective and can't effectively remove harmful aggregates. In such conditions, the forced activation of HSF1 and its targeted molecular chaperone proteins, such as HSPs, by using various plant-derived compounds, such as celastrol, curcumin, and resveratrol, has shown promising neuroprotective effects by eliminating protein aggregates across multiple AD models. Hence, this review focused on various plant-derived compounds and their mode of activating HSF1 and its encoded HSPs. This review also described other compounds from multiple natural sources that affect HSF1 and HSPs in different disease models. In this way, the current review will be a complete reference for natural compounds that activate HSF1 and help researchers identify potential drug candidates for NDs like Alzheimer's disease.

Keywords:  Alzheimer's disease; Clear protein aggregates; Modulators of HSF1; Natural compounds; Neuroprotection; Pathogenesis; Phytocompounds; Protein aggregates; UPS

DOI:  https://doi.org/10.1016/j.ejphar.2025.178034
bioRxiv. 2025 Jul 24. pii: 2025.07.21.665894. [Epub ahead of print]

Impairment of neuronal activity occurs at the early stages of the aggregation cascade of Aβ 1-42 and mutant Tau.

Franziska Hirsch, Nino Läubli, Anushree Kelkar, Mira Sleiman, Yvonne Woitzat, Christian Gallrein, Vanessa Gumz, Gurleen Kaur Kalsi, Ana Fernandez-Villegas, Gabriele Kaminski Schierle, Janine Kirstein.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary Tau tangles, ultimately leading to brain atrophy and death. To elucidate the relationship between the aberrant folding and aggregation of Aβ and mutant Tau and neuronal function, we monitored neuronal activity in C. elegans AD models across age. Our findings reveal that expression of both Aβ and Tau lead to significant reductions in neuronal activity and function in young adult animals preceding the accumulation of amyloid aggregates. Notably, Aβ expression and aggregation in muscle tissue produced comparable detrimental effects on neuronal activity as its expression in neurons, suggesting that proteotoxic stress in muscle can influence neuronal function. This may occur through the propagation of Aβ from muscle to neurons or through retrograde signaling pathways. Further, our new sub-stoichiometrically labeled Tau strains highlight that Tau P301L,V337M has a significant impact on neuronal activity throughout aging. These results enhance our understanding of the early functional effects of amyloid aggregation in Alzheimer's disease.

DOI: https://doi.org/10.1101/2025.07.21.665894
bioRxiv. 2025 Jul 31. pii: 2025.07.30.667758. [Epub ahead of print]

Modulation of biomolecular aggregate morphology and condensate infectivity.

Josephine C Ferreon, Kyoung-Jae Choi, My Diem Quan, Phoebe S Tsoi, Cristopher C Ferreon, Ulas Coskun, Shih-Chu Jeff Liao, Allan Chris M Ferreon.

Neurodegenerative diseases are characterized by pathological aggregates exhibiting distinct morphologies, such as neurofibrillary tangles and dense circular Lewy body-like structures in Alzheimer's disease, and round hyaline gel-like inclusions and skein-like filaments in amyotrophic lateral sclerosis. However, the mechanisms driving the formation of these diverse morphological structures remain poorly understood. Employing advanced microscopy, including fluorescence lifetime imaging, we investigated condensate aging and aggregation mechanisms of the prion-like domain of hnRNPA1 (A1PrD), a ribonucleoprotein implicated in both disorders. Using a simplified system across various salt and RNA conditions, we demonstrate that homotypic and heterotypic interactions between A1PrD and RNA significantly influence aggregate morphology and amyloid fibril formation, yielding diverse structures including thin fibrils, solid gels, and filamentous starburst aggregates. By tracking aggregate morphogenesis, we observed shifts in fluorescence lifetimes that reflect differences in condensate microenvironments, highlighting distinct homotypic and heterotypic interaction dynamics. Our findings indicate that amyloid fibril formation can initiate within fluid condensates or at the interfaces of solid gels. Moreover, early amyloid-rich fluid starbursts demonstrated the capability to fuse with or recruit younger amyloid-poor droplets, exemplifying prion-like infectivity and accelerating fibril formation. Collectively, our study provides evidence that the interplay between solution composition and the kinetic balance of liquid-liquid phase separation, gelation, and fibrillation contributes to the diverse pathological aggregate morphologies observed in neurodegenerative diseases.

DOI: https://doi.org/10.1101/2025.07.30.667758
Front Biosci (Landmark Ed). 2025 Jul 07. 30(7): 27178

Alpha-Synuclein Dysregulation in Systemic Pathophysiology of Synucleinopathies.

Hallie H Dolin, Bowen Zhou, Robert W Maitta.

  Alpha-synuclein (α-syn) has long been identified as the etiologic agent of multiple neurodegenerative diseases, the most common and well-known of which are Parkinson's disease (PD) and Lewy body dementia (LBD). While it is known that the pathophysiology of these synucleinopathies involves aggregation of improperly-folded α-syn, the mechanisms leading to its accumulation have not been fully identified. However, multiple pathways have been proposed, any or all of which may contribute to synucleinopathies. The role of α-syn in normal homeostasis and in other organ systems, especially the hematopoietic system, has been reported recently. Research within the last decade has shown that α-syn plays many vital and conserved roles in the cell biology of various organ systems, such as packaging of cell products, exocytosis, membrane stabilization, and more. This protein has been recognized as an essential factor in normal hematopoietic and immune systems function, and its deficiency leads to an abnormal phenotype, in hematopoietic and immune cell lineages. Similar phenotypes in synucleinopathies not only emphasize the conserved nature of the synuclein family but suggest a bimodal pathophysiology in which aggregated α-syn leads to cellular toxicity while causing derangement of systems that require it. Research into specific molecular mechanisms and potential treatments may provide further understanding of neurodegenerative diseases as well as lead to novel therapies. However, elucidation of the systemic roles of α-syn in addition to its toxicity in excess is essential to prevent treatment-induced deprivation, which paradoxically harms the patient. Here, we address recent advances in systemic synucleinopathies and putative interconnectedness of these compartments. While previous studies and reviews have focused on the mechanisms of α-syn synthesis, transport, and aggregation within systems, this review focuses on the potential inter-systemic nature of synucleinopathies and their possible synergistic origins.

Keywords:  Parkinson’s disease; hematopoiesis; immunity; neurodegenerative disease; synucleinopathies; α-synuclein

DOI:  https://doi.org/10.31083/FBL27178
bioRxiv. 2025 Jul 31. pii: 2025.07.30.667669. [Epub ahead of print]

Cytoplasmic TDP-43 leads to early functional impairments without neurodegeneration in a Serotonergic Neuron-Specific C. elegans Model.

Ailín Lacour, Florencia Vassallu, Diego Rayes, Lionel Muller Igaz.

TDP-43 proteinopathies, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are marked by the pathological cytoplasmic accumulation of TAR DNA-binding protein 43 (TDP-43), leading to progressive neuronal dysfunction and degeneration. To investigate the early functional consequences of TDP-43 mislocalization, we generated Caenorhabditis elegans models expressing either wild-type human TDP-43 or a variant with a mutated nuclear localization signal (ΔNLS), specifically in serotonergic neurons. These neurons were chosen because i) serotonin deficits are a feature of ALS/FTD and ii) in C. elegans , they regulate well-characterized behaviors, providing a straightforward readout of neuronal function. We found that expression of either TDP-43 variant impaired serotonin-dependent behaviors-including pharyngeal pumping, egg-laying, and locomotion slowing upon food encounter-with the cytoplasmic ΔNLS form causing more severe deficits. Serotonergic neurons remained i) morphologically intact, indicating that neuronal dysfunction precedes overt neurodegeneration; and ii) partially responsive to the selective serotonin reuptake inhibitor fluoxetine, suggesting that neurotransmitter release is still partially functional. Altogether, our findings demonstrate that cytoplasmic TDP-43 disrupts neuronal signaling and behavior early in disease progression. This C. elegans model provides a genetically tractable system to dissect early mechanisms of TDP-43-mediated dysfunction and to identify therapeutic strategies targeting predegenerative stages of ALS/FTD.

DOI: https://doi.org/10.1101/2025.07.30.667669
J Phys Chem B. 2025 Aug 04.

Aggregation of TDP-43307-319: A Dual Pathway to Forming Cylindrins and Fibrils and a Contribution to the Etiology of Amyotrophic Lateral Sclerosis.

Yingying Jin, Pritam Ganguly, Joan-Emma Shea, Steven K Buratto, Michael T Bowers.

The pathological aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) is a hallmark of amyotrophic lateral sclerosis, and mutations within its low-complexity domain are known to influence its aggregation propensity and toxicity. Previous studies from our group and others have shown that TDP-43307-319 located at the C-terminus of TDP-43 is toxic and can form higher-order oligomers and fibrils. Of particular interest are the hexamers, which adopt a cylindrin structure that has been strongly correlated to neurotoxicity. In this study, we used a combination of ion mobility spectroscopy-mass spectrometry (IMS-MS), atomic force microscopy (AFM), and molecular dynamics simulations to probe the oligomer distribution resulting from the earliest times (the first 5 to 15 min) of incubation at varying concentrations for three different TDP-43307-319 mutations: wild-type (WT), A315T, and G314V. In this way, it was possible to trace the oligomer distributions at the initial stages of aggregation while avoiding the complication from aggregation-induced sedimentation over long periods. We found that both WT and A315T rapidly form stable hexamers and higher-order oligomers at low concentrations. As the concentration is increased, the IMS-MS oligomer distribution changes to favor small oligomers over the hexamers and higher-order oligomers for both WT and A315T. AFM shows that this shift in oligomer distribution is due to the formation of fibrils that are seeded by trimers and tetramers. This complex concentration dependence is attributed to two different kinetic paths: one at low concentration that favors the formation of hexamers/cylindrins and one at high concentration that favors fibril formation. Furthermore, the G314V mutation is nontoxic and does not show evidence of the two kinetic paths as hexamers are not formed at any concentration whereas fibril formation is observed at all concentrations.

DOI: https://doi.org/10.1021/acs.jpcb.5c02640
bioRxiv. 2025 Jul 21. pii: 2025.07.16.665194. [Epub ahead of print]

mGluR4-Npdc1 complex mediates α-synuclein fibril-induced neurodegeneration.

Azucena Perez-Canamas, Mingming Chen, Leire Almandoz-Gil, Nabab Khan, Si Jie Tang, Allyson Ho, Erik C Gunther, Stephen M Strittmatter.

Fibrils of misfolded α-synuclein (α-syn) accumulate in Parkinson's disease and other synucleinopathies, spreading between cells to template further misfolding and drive neurodegeneration. α-syn fibril entry into healthy neurons is recognized as a key step in the disease process but remains ill-defined mechanistically. Here, we comprehensively assessed the membrane proteome for binding of α-syn fibrils. Expression cloning identified mGluR4 and Npdc1 as plasma membrane proteins expressed by substantia nigra neurons capable of supporting high affinity α-syn fibril binding. Moreover, mGluR4 and Npdc1 cellular signaling functions were titrated by the presence of extracellular fibrillary α-syn. While striatal α-syn fibril injection led to nigral dopamine neuron loss in wild type mice, deletion of either Grm4 or Npdc1 provided protection of dopamine neurons. We observed mGluR4 and Npdc1 to form a complex that regulates mGluR4 signaling. Cultured neurons lacking both Grm4 and Npdc1 fail to bind α-syn fibrils, to accumulate phosphorylated α-syn and to lose synapses. Transheterozygous Grm4 , Npdc1 mice showed protection from nigral neuron loss after striatal α-syn injection, demonstrating genetic interaction between the two binding proteins. On a transgenic α-syn A53T background, double Grm4 , Npdc1 heterozygosity robustly increased mouse survival, motor function and spinal motoneuron number. Thus, a cell surface mGluR4-Npdc1 complex participates in α-syn neurodegeneration.

DOI: https://doi.org/10.1101/2025.07.16.665194
Int J Biol Macromol. 2025 Aug 03. pii: S0141-8130(25)06955-7. [Epub ahead of print] 146398

Berberine mitigates neurotoxicity of misfolded protein oligomers by interacting with the cell membrane and subsequent internalization, without altering their structure.

Silvia Errico, Giulia Fani, Martina Gennari, Alessandra Mastricci, Lorenzo Neri, Davide Odino, Claudio Canale, Annalisa Relini, Michele Vendruscolo, Benedetta Mannini, Fabrizio Chiti.

  Numerous neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, are associated with the misfolding and aggregation of proteins. In this study, we investigate the protective role of the natural alkaloid berberine against protein misfolded aggregates, given its potential as a therapeutic agent. Our findings demonstrate that berberine binds to the lipid membranes of reconstituted liposomes with diverse lipid compositions and can cross lipid membranes via diffusion. Correspondingly, in cultured human neuroblastoma cells, berberine interacts with the plasma membrane and is rapidly internalized into the cytoplasm. Furthermore, berberine exhibited rapid and dose-dependent protective effects upon exposing LUVs or cells to misfolded protein aggregates able to induce lipid membrane damage. Specifically, in human neuroblastoma cells pre-treated with berberine, the molecule reduced plasma membrane alterations and the associated Ca2+ ion influx, diminished the production of reactive oxygen species, and reduced mitochondrial metabolism dysfunction, induced by the aggregates. Concomitant administration of berberine and aggregates was not found to be protective against aggregates and moreover, berberine does not significantly modify the structure of the protein aggregates, suggesting that its protective effect against these aberrant species in cells is due to its ability to rapidly interact with and cross the cell membrane. Together, these findings provide insight into the mechanism of protective action of berberine and support its therapeutic potential in mitigating cellular damage associated with protein aggregation.

Keywords:  Amyloid; Natural products; Protein misfolding; Protein oligomers; Proteotoxicity

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.146398
bioRxiv. 2025 Jul 23. pii: 2025.07.18.665492. [Epub ahead of print]

A Bioinformatic Analysis of BAG Protein Interactors and Pathways in Alzheimer's and Parkinson's Disease.

Sudarshan Ramanan, Gail Vw Johnson.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders. While the symptoms and general etiology may be different, these two diseases share significant common features in terms of their disease pathogenesis. Within the scope of neurodegenerative disorders, the Bcl-2 associated athanogene (BAG) family proteins and associated interactors have been a key area of focus. The BAG family is a group of proteins that contain at least one evolutionarily conserved BAG domain. Despite this similarity, their interactions and functions can vary widely. So far, research has predominantly scrutinized individual BAG proteins, rather than explore potential cooperative actions among family members. Some BAG family members may function together thereby indicating potential interactions within this family. Although connections among BAG members have been observed, their role in neurodegenerative disorders, such as AD and PD, remains largely uncharacterized. This mini review explores the common pathways, intersections, and differences within these interactions as well as their link to AD and PD. Using computational techniques to mine transcriptomic data, several groupings of pathways that these BAG family members are involved in were identified in the context of AD and PD. Understanding these pathways and their relationships may uncover potential gaps in current research and help identify novel therapeutic targets for the treatment of these neurodegenerative diseases.
Significance statement: Although distinct diseases, Alzheimer's disease and Parkinson's disease share common features such as protein aggregation and mitochondrial dysfunction. Members of the BAG family of proteins have been implicated in the pathogenesis of both diseases. Computational techniques were used to mine transcriptomic data of Alzheimer's and Parkinson's disease cases to identify common pathways. BAG protein interactors, common to all family members, were analyzed in the context of these common pathways for Alzheimer's and Parkinson's disease. These analyses provide insights into the pathways mediated by these BAG protein interactors that are likely at the intersection of Alzheimer's disease and Parkinson's disease pathologies.

DOI: https://doi.org/10.1101/2025.07.18.665492
Acta Naturae. 2025 Apr-Jun;17(2):17(2): 110-117

Monomeric α-Synuclein Real-Time Induced Conversion: A New Approach to the Diagnostics of Neurodegenerative Synucleinopathies with Weak RT-QuIC Responses.

D A Orlova, A A Kudriaeva, N A Kolotyeva, E O Ivanova, E Yu Fedotova, P P Tregub, A B Salmina, S N Illarioshkin, A A Belogurov Jr.

  Neurodegenerative disorders classified as synucleinopathies (Parkinson's disease, dementia with Lewy bodies, and multiple-system atrophy) are characterized by the accumulation of aberrant α-synuclein aggregates in neurons and glial cells. These diseases manifest clinically several years after the initial formation of pathological protein aggregates in the brain, making early and accurate diagnosis challenging. In recent years, a new method, which is based on real-time quaking-induced conversion (RT-QuIC) of α-synuclein, has been developed and validated. This technology holds great promise as a powerful diagnostic tool for the early and precise identification of synucleinopathies, potentially opening new horizons in the study of neurodegenerative diseases. RT-QuIC detects misfolded α-synuclein aggregates in human physiological fluids by introducing an excess of recombinant α-synuclein, which undergoes conformational conversion in an exponential, prion-like manner. The production of high-quality recombinant α-synuclein is a critical step in the effective application of this method, as protein purity significantly affects the sensitivity and specificity of the assay - key factors in its diagnostic utility. Using a three-step chromatographic purification protocol, we produced recombinant monomeric α-synuclein with a purity exceeding 97% from the periplasmic fraction of bacterial cells. While higher purity increases the assay duration, it also reduces the background signal and permits extended incubation times, which are essential for reliably detecting synucleinopathies with weak RT-QuIC responses, such as the cerebellar subtype of multiple-system atrophy. The data presented support the conclusion that optimized components of the RT-QuIC system will enable an accurate diagnosis of neurodegenerative synucleinopathies.

Keywords:  Lewy body dementia; diagnostics; multiple system atrophy; real-time quakinginduced conversion (RT-QuIC); synucleinopathies; α-synuclein

DOI:  https://doi.org/10.32607/actanaturae.27530
Front Aging Neurosci. 2025 ;17 1604378

NMDA receptors in neurodegenerative diseases: mechanisms and emerging therapeutic strategies.

Keyi Zhang, Ming Wen, Xinyue Nan, Shuaizhu Zhao, Hao Li, Yanping Ai, Houze Zhu.

  NMDA receptors (NMDARs) are widely distributed throughout the central nervous system (CNS) and play pivotal roles in normal physiological processes such as synaptic plasticity, learning, and memory. Substantial evidence indicates that NMDAR dysfunction, particularly excessive calcium influx, critically contributes to the pathogenesis of major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Dysregulated glutamatergic signaling synergizes with pathological protein aggregation (e.g., Aβ, α-synuclein, mutant huntingtin) to drive neuronal loss. We systematically delineate NMDAR-related mechanisms underlying neurodegeneration, highlighting spatial-specific roles (e.g., synaptic NMDAR-mediated neuroprotection versus extrasynaptic NMDAR-mediated excitotoxicity) and crosstalk with mitochondrial dysfunction and oxidative stress. We critically evaluate current therapeutic strategies targeting NMDARs, including subunit-selective modulators, downstream effector modulation, and glutamate transporter modulation designed to restore NMDAR homeostasis. Consequently, NMDARs and their modulators represent promising therapeutic targets for these refractory conditions. This review comprehensively summarizes current research on the involvement of NMDARs and the glutamatergic system in neurodegenerative diseases. Furthermore, we discuss the clinical application of NMDAR-targeting agents and explore emerging therapeutic strategies focused on modulating NMDAR-related pathways. This article aims to provide a reference for elucidating the molecular mechanisms underlying these neurodegenerative disorders and to highlight potential avenues for future drug development.

Keywords:  Alzheimer’s disease (AD); Huntington’s disease (HD); NMDA receptors (N-methyl-D-aspartate receptors); Parkinson’s disease (PD); amyotrophic lateral sclerosis (ALS); excitotoxicity; glutamate; neurodegenerative disease

DOI:  https://doi.org/10.3389/fnagi.2025.1604378
J Am Chem Soc. 2025 Aug 06.

α-Synuclein Drives SNARE-Dependent Tubular Remodeling of Vesicles.

Qun Li, Tao Hu, Fan Li, Yutong Xing, Zhenyong Wu.

α-Synuclein (α-syn) disrupts synaptic vesicle architecture in Parkinson's disease (PD), yet the underlying mechanisms remain unclear. Here, we identify a previously unrecognized phenomenon in which α-syn (≥20 μM) rapidly induces SNARE-dependent tubular protrusions on highly curved small unilamellar vesicles (∼45 nm in diameter). This process requires functional v- and t-SNAREs, as neither v-SNARE nor t-SNARE alone, nor predocked SNARE complexes or CDV-treated SNARE liposomes, support tubulation. Notably, the familial PD-associated mutations A30P and E46K enhance tubule formation, whereas A53T exhibits minimal activity. Disrupting the α-syn-VAMP2 interaction abolishes tubulation, directly linking this interface to vesicle remodeling. Tubule formation increases with α-syn concentration, impairs SNARE-mediated membrane fusion, and significantly modulates α-syn liquid-liquid phase separation (LLPS), underscoring its pathological relevance. These findings reveal a novel mechanism by which α-syn remodels vesicle architecture, providing deeper insights into synaptic dysfunction in PD.

DOI: https://doi.org/10.1021/jacs.5c06021
NPJ Parkinsons Dis. 2025 Aug 06. 11(1): 231

Regulation of polyamine interconversion enzymes affects α-Synuclein levels and toxicity in a Drosophila model of Parkinson's Disease.

Bedri Ranxhi, Zoya R Bangash, Zachary M Chbihi, Zaina Qadri, Nazin N Islam, Sokol V Todi, Peter A LeWitt, Wei-Ling Tsou.

Parkinson's Disease (PD) is a neurodegenerative disorder characterized by α-synuclein accumulation and aggregation, leading to disrupted cellular homeostasis, impaired mitochondrial function, and neuroinflammation, ultimately causing neuronal death. Recent biomarker studies reveal elevated serum levels of L-ornithine-derived polyamines correlating with PD progression and clinical subtypes, though their precise role in PD pathology remains unclear. We investigated the impact of polyamine-interconversion enzymes (PAIEs) on α-synucleinopathy in a Drosophila melanogaster model of PD, evaluating key degenerative features such as lifespan, locomotor function, tissue integrity, and α-synuclein accumulation. Knockdown of ornithine decarboxylase 1 (ODC1), spermidine synthase (SRM), and spermine oxidase (SMOX) reduced α-synuclein toxicity, while suppression of spermidine/spermine N1-acetyltransferase 1 (SAT1) and spermine synthase (SMS) exacerbated it. Conversely, overexpressing SAT1 or SMOX significantly reduced α-synuclein toxicity, highlighting their potential role in PD. These findings underscore the critical role of polyamine pathways in modulating α-synuclein toxicity, offering novel therapeutic targets for PD.

DOI: https://doi.org/10.1038/s41531-025-01087-9
NPJ Parkinsons Dis. 2025 Aug 04. 11(1): 228

Elevated plasma levels of alpha-synuclein are dispensable for Parkinson's disease pathology.

Jin-Young Jeong, Namsuk Kim, Yan Li, Doo-Jin Kim, Hyong Kyu Kim, Won-Jong Oh.

Although α-synuclein levels are elevated in the blood plasma of Parkinson's disease (PD) patients, it remains unclear whether blood-derived α-synuclein directly contributes to PD. To investigate this, we developed a novel mouse model in which human α-synuclein levels are increased in the blood. Despite a significant increase in α-synuclein in the blood, no noticeable behavioral abnormalities were observed in aged mice. Additionally, we did not observe plasma α-synuclein aggregation in the blood or entry of human α-synuclein into the brain. These results suggest that elevated blood levels of α-synuclein may not be sufficient to induce PD progression.

DOI: https://doi.org/10.1038/s41531-025-01091-z
NPJ Parkinsons Dis. 2025 Aug 07. 11(1): 232

Phosphorylated α-synuclein in CSF and plasma does not reflect synucleinopathy.

Giovanni Bellomo, Erik Stoops, Jeroen Vanbrabant, Leentje Demeyer, Cindy Francois, Melanie Vanhooren, Yihua Ma, Carly M Farris, Luis Concha-Marambio, Federico Paolini Paoletti, Lorenzo Gaetani, Lucilla Parnetti, Davide Chiasserini.

We developed a highly sensitive and specific single-molecule array (Simoa) Homebrew assay for quantification of phosphorylated α-synuclein at serine 129 (pS129 α-syn) and evaluated its performance in human cerebrospinal fluid (CSF) and plasma. Using a cohort of patients with Parkinson's disease (PD), Alzheimer's disease (AD), and neurological controls with available CSF α-synuclein seed amplification assay (synSAA) outcome, we examined pS129 α-syn alongside N-terminal and C-terminal α-syn proteoforms. Our results showed that pS129 α-syn concentration was about 1% and 0.001% of the other α-syn species in CSF and plasma, respectively. We found no correlation between pS129 α-syn and synSAA outcome, indicating that soluble pS129 α-syn in CSF and plasma does not reflect presence of synucleinopathy. Interestingly, pS129 α-syn and other α-syn forms were significantly increased in AD compared to PD and controls, supporting the role of α-syn as biomarker of synaptic degeneration in AD.

DOI: https://doi.org/10.1038/s41531-025-01086-w
Biophys J. 2025 Aug 06. pii: S0006-3495(25)00491-6. [Epub ahead of print]

The role of hydrophobic collapse in cytotoxic and functional amyloid oligomerization.

Kelsie M King, Hajar Zaheer, Anne M Brown.

  Amyloid refers to an insoluble, highly organized protein fibril composed of intermolecular β-sheets, known as a cross-β motif. Amyloidogenic proteins are generally driven to aggregate into tightly packed fibrils. Some amyloids are functional, often being utilized as hormone storage reservoirs. The functional, paracrine signaling neuropeptide β-endorphin (βE) is stored and released to modulate pain responses. Conversely, the function of amyloid-β (Aβ), involved in Alzheimer's disease, is uncertain - but substantial evidence exists of its role in neuronal cell apoptosis. While both peptides are mechanistically linked in their propensity to adopt fibrillar structures, the biophysical characteristics that drive divergence in cytotoxic potential are not well understood. To probe the conformational dynamics and mechanisms of functional and cytotoxic oligomer formation, we utilized all-atom molecular dynamics (MD) to simulate the formation of monomeric and hexameric Aβ42 and βE31. Monomeric Aβ42 and βE31 selectively sampled β-strand motifs comprised of hydrophobic residues, adopting a collapsed state. Cluster analysis indicates that βE31 hexamers were more conformationally diverse than those sampled by Aβ42, suggesting βE31 exhibits more signatures of disorder. Aβ42 hexamer formation was driven by hydrophobic packing of collapsed β-strand motifs, where βE31 hexamer peptide subunits remained structurally plastic and solvent accessible. Mutation of Aβ42 disrupting the C-terminal hydrophobic sequence inhibited hydrophobic β-strand formation, reduced aggregation propensity and increased solvent accessibility, suggesting retention of a collapsed state is critical for aberrant oligomer formation. This work provides a preliminary view of cytotoxic and functional oligomer morphologies at atomistic resolution, gaining insights into the biophysical aspects of early aggregation events of amyloids.

Keywords:  amyloid; amyloid-β; intrinsically disordered proteins; molecular dynamics (MD) simulations; β-endorphin

DOI:  https://doi.org/10.1016/j.bpj.2025.07.042
Sci Rep. 2025 Aug 04. 15(1): 28446

Aggregation potency and proinflammatory effects of SARS-CoV-2 proteins.

Monica Costa, Da-Wei Wang, Kai-Dong Zhao, Lin Yuan, Anita Krisko, Jia-Yi Li, Tiago Outeiro, Wen Li.

  Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is primarily known as a respiratory disease. The continued study of the disease has shown that long-term COVID-19 symptoms include persisting effects of the virus on the brain when the infection is over, possibly even leading to neurodegeneration. However, the exact mechanisms of nervous system damage induced by SARS-CoV-2 are still unclear. In this study, we focused on two possibly shared pathways of SARS-CoV-2-induced neural dysfunction and neurodegeneration: protein aggregation, which is associated with impaired protein clearance, and inflammatory responses, which involve a hyper-active immune status. We observed distinct expression and distribution patterns of ten SARS-CoV-2 proteins in the two cell lines, meanwhile forming aggregation puncta and inducing pro-inflammatory responses. We found that the ER stress was induced and that the autophagy-lysosome pathway was inhibited upon viral protein expression. Boosting autophagy function attenuated protein aggregation, suggesting that modulation of autophagy might be a valid strategy for inhibiting cytotoxic effects of SARS-CoV- 2 proteins. Our study provides potential explanations of SARS-CoV-2-induced cell damage, based on shared cellular mechanisms and furthermore, suggests that modulation of proteostasis may serve as therapeutic strategies for preventing long-lasting SARS-CoV-2 cytotoxic effects.

Keywords:  Coronavirus disease 2019; Inflammation; Neurodegeneration; Protein aggregation; SARS-CoV-2 protein

DOI:  https://doi.org/10.1038/s41598-025-10013-1
Nat Struct Mol Biol. 2025 Aug 08.

Structural analyses define the molecular basis of clusterin chaperone function.

Patricia Yuste-Checa, Alonso I Carvajal, Chenchen Mi, Sarah Paatz, F Ulrich Hartl, Andreas Bracher.

Clusterin (apolipoprotein J), a conserved glycoprotein abundant in blood and cerebrospinal fluid, functions as a molecular chaperone and apolipoprotein. Dysregulation of clusterin is linked to late-onset Alzheimer disease. Despite its prominent role in extracellular proteostasis, the mechanism of clusterin function remained unclear. Here, we present crystal structures of human clusterin, revealing a discontinuous three-domain architecture. Structure-based mutational analysis demonstrated that two disordered, hydrophobic peptide tails enable diverse activities. Resembling the substrate-binding regions of small heat-shock proteins, these sequences mediate clusterin's chaperone function in suppressing amyloid-β, tau and α-synuclein aggregation. In conjunction with conserved surface areas, the tail segments also participate in clusterin binding to cell surface receptors and cellular uptake. While contributing to lipoprotein formation, the hydrophobic tails remain accessible for chaperone function in the lipoprotein complex. The remarkable versatility of these sequences allows clusterin to function alone or bound to lipids in maintaining the solubility of aberrant extracellular proteins and facilitating their clearance by endocytosis and lysosomal degradation.

DOI: https://doi.org/10.1038/s41594-025-01631-4
Commun Biol. 2025 Aug 07. 8(1): 1179

Lipid packing defects are necessary and sufficient for membrane binding of α-synuclein.

David H Johnson, Orianna H Kou, John M White, Stephanie Y Ramirez, Antonis Margaritakis, Peter J Chung, Vance W Jaeger, Wade F Zeno.

α-Synuclein (αSyn), an intrinsically disordered protein implicated in Parkinson's disease, is thought to initiate aggregation by binding to cellular membranes. Previous studies suggest that anionic lipids are necessary for this binding. However, these studies largely focused on unmodified αSyn, while physiological αSyn is N-terminally acetylated (NTA). Our work challenges the long-standing paradigm that anionic lipids are necessary for αSyn binding by demonstrating that NTA diminishes αSyn's reliance on anionic membranes, revealing that membrane packing defects (i.e., interfacial hydrophobicity) alone can drive membrane binding. Using fluorescence microscopy and circular dichroism spectroscopy, we monitored the binding of NTA-αSyn to membrane vesicles with different lipid compositions. Phosphatidylcholine and phosphatidylserine concentrations were varied to control surface charge, while phospholipid tail unsaturation and methylation were varied to modulate lipid packing. We also formulated cholesterol-containing membranes that mimicked the lipid composition of synaptic vesicles. In these membranes, all-atom molecular dynamics simulations were used to visualize and quantify membrane packing defects. Our results demonstrate that membrane packing defects are necessary for NTA-αSyn binding and that defect-rich membranes are sufficient for NTA-αSyn binding regardless of membrane charge. These findings provide a molecular mechanism by which lipid structural properties, such as poly-unsaturation, can regulate αSyn binding to physiological membranes.

DOI: https://doi.org/10.1038/s42003-025-08622-7
Front Mol Biosci. 2025 ;12 1639327

Deuterium trafficking, mitochondrial dysfunction, copper homeostasis, and neurodegenerative disease.

Stephanie Seneff, Anthony M Kyriakopoulos.

  Deuterium is a natural heavy isotope of hydrogen, containing an extra neutron. Eukaryotic organisms have devised complex metabolic policies that restrict the amount of deuterium reaching the mitochondria, because it damages the ATPase pumps, leading to release of excessive reactive oxygen species and inefficiencies in ATP production. Human metabolism relies heavily on the gut microbiome to assure an abundant supply of deuterium depleted (deupleted) nutrients to the host. Mitochondrial dysfunction is a hallmark of many chronic diseases, and deuterium overload, often due to gut dysbiosis, may be a major factor contributing to this issue. In this paper, we explore the potential role of certain amyloidogenic proteins, including amylin, amyloid beta, the prion protein, huntingtin, and α-synuclein, in disease processes that result in the accumulation of deposits of protein fibrils, along with lipid membrane components of damaged mitochondria, which we argue may be a mechanism to sequester deuterium in order to reduce the deuterium burden in the tissues. We show how cardiolipin, an anionic lipid synthesized in mitochondria and localized to the mitochondrial membrane, may play a central role both in trapping deuterium in the mitochondrial membrane and in inducing protein misfolding to facilitate the formation of deuterium-rich deposits. We focus on the potential role of the amino acid histidine and its interaction with the mineral copper, both to catalyze certain essential reactions and to facilitate the misfolding of amyloidogenic proteins triggered by contact with anionic phospholipids, particularly cardiolipin, and especially in the outer mitochondrial membrane of deuterium-damaged mitochondria.

Keywords:  amyloidogenic proteins; cardiolipin; copper; deuterium; histidine; mitochondrial dysfunction; neurodegeneration

DOI:  https://doi.org/10.3389/fmolb.2025.1639327
Alzheimers Dement. 2025 Aug;21(8): e70497

Diabetic retinopathy and Alzheimer's disease: Convergence of the unfolded protein response in neurodegeneration.

Adrián G Palacios, Sarah X Zhang, Mónica L Acosta.

  Diabetic retinopathy (DR) and Alzheimer's disease (AD) are progressive neurodegenerative disorders affecting the eye and the brain, respectively. Despite targeting different organs, they share common molecular mechanisms. A central process connecting these conditions is the unfolded protein response (UPR), which maintains protein homeostasis in the endoplasmic reticulum (ER). Dysregulation of UPR pathways, particularly the IRE1-XBP1 and PERK-eIF2α pathways, can lead to inflammation, oxidative stress, and neurodegeneration. While the IRE1-XBP1 pathway regulates protein folding and inflammatory signaling, the PERK-eIF2α pathway reduces protein synthesis but may trigger apoptosis if persistently activated. Emerging therapies targeting UPR pathways and ER chaperones show promise in mitigating neurodegenerative damage in DR and AD. This review highlights shared pathophysiological mechanisms, explore retinal biomarkers for early AD detection, and emphasizes UPR modulation as a therapeutic strategy for neurodegeneration in aging-related diseases. HIGHLIGHTS: Diabetic retinopathy (DR, ocular disorder) and Alzheimer's disease (AD, cerebral disorder) share common molecular mechanisms, including oxidative stress, inflammation, and proteostasis dysfunction. UPR is a critical pathway linking both diseases through endoplasmic reticulum (ER) stress and neurodegeneration and targeting unfolded protein response (UPR) pathways, ER chaperones (e.g., P58IPK), and anti-inflammatory treatments show promise. The IRE1-XBP1 pathway regulates protein homeostasis and inflammation; XBP1s protects against ER stress in both retinal and brain neurons. The PERK-eIF2α pathway suppresses protein synthesis under stress but may induce apoptosis via ATF4 and CHOP if chronically activated. Age-related decline in metabolism, proteostasis, and neurovascular function intensifies disease progression and exacerbates molecular and cellular damage in both DR and AD.

Keywords:  Alzheimer's disease; aging; diabetes; retina; unfolded protein response

DOI:  https://doi.org/10.1002/alz.70497
Nat Neurosci. 2025 Aug 06.

Hypoxia ameliorates neurodegeneration and movement disorder in a mouse model of Parkinson's disease.

Eizo Marutani, Maria Miranda, Timothy J Durham, Sharon H Kim, Dreson L Russell, Presli P Wiesenthal, Paul Lichtenegger, Marissa A Menard, Charlotte F Brzozowski, Haobo Li, Gary Ruvkun, Joshua D Meisel, Laura Volpicelli-Daley, Vamsi K Mootha, Fumito Ichinose.

Parkinson's disease (PD) is characterized by inclusions of α-synuclein (α-syn) and mitochondrial dysfunction in dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc). Patients with PD anecdotally experience symptom improvement at high altitude; chronic hypoxia prevents the development of Leigh-like brain disease in mice with mitochondrial complex I deficiency. Here we report that intrastriatal injection of α-syn preformed fibrils (PFFs) in mice resulted in neurodegeneration and movement disorder, which were prevented by continuous exposure to 11% oxygen. Specifically, PFF-induced α-syn aggregation resulted in brain tissue hyperoxia, lipid peroxidation and DA neurodegeneration in the SNpc of mice breathing 21% oxygen, but not in those breathing 11% oxygen. This neuroprotective effect of hypoxia was also observed in Caenorhabditis elegans. Moreover, initiating hypoxia 6 weeks after PFF injection reversed motor dysfunction and halted further DA neurodegeneration. These results suggest that hypoxia may have neuroprotective effects downstream of α-syn aggregation in PD, even after symptom onset and neuropathological changes.

DOI: https://doi.org/10.1038/s41593-025-02010-4