bims-proned 2025-05-25 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–05–25
ten papers selected by
Verena Kohler, Umeå University

Mechanism of flavonoid myricetin modulated aggregation in α-Synuclein and its familial mutants E46K and A30P.
Epigallocatechin-3-gallate binds tandem RNA recognition motifs of TDP-43 and inhibits its aggregation.
Virus-like particles of retroviral origin in protein aggregation and neurodegenerative diseases.
Small HSPs at the crossroad between protein aggregation, autophagy and unconventional secretion: clinical implications and potential therapeutic opportunities in the context of neurodegenerative diseases.
Regulating aggregation of an intrinsically disordered chaperone-like casein.
Autophagy dysfunction and neurodegeneration: Where does it go wrong?
Alpha-synuclein aggregates trigger cardiolipin externalization and mitophagy.
Endoplasmic Reticulum Stress Induces Liquid-Liquid Phase Separation of GRP78 and Modulates Protein Aggregation Dynamics.
Inhibition of tau aggregation by the CCT3 and CCT7 apical domains.
Exploring α-Syn's Functions Through Ablation Models: Physiological and Pathological Implications.

Arch Biochem Biophys. 2025 May 16. pii: S0003-9861(25)00183-3. [Epub ahead of print]770 110470

Mechanism of flavonoid myricetin modulated aggregation in α-Synuclein and its familial mutants E46K and A30P.

Tinku, Anitadevi K Prajapati, Satrujeet Sahoo, G Deepak, Soumya Nair, Sinjan Choudhary.

  Inhibiting the aggregation of α-Synuclein (α-Syn) and its familial mutants E46K and A30P has emerged as one of the effective therapeutic strategies against Parkinson's disease (PD). The inhibition and modulation of α-Syn/E46K/A30P fibrillation as well as disaggregation of their pre-formed fibrils by a natural flavonoid myricetin (Myr) is studied. The binding of Myr with α-Syn and its mutants with the affinity ranging 104-105 M-1. The isothermal titration calorimetry (ITC) results indicate the involvement of hydrogen binding/ionic and hydrophobic interactions in the binding process. The aggregation kinetics studies demonstrate that Myr inhibits aggregation of α-Syn/E46K/A30P in a concentration dependent manner. Seeding experiments demonstrate that the protein aggregates formed in the presence of Myr do not further instigates aggregation in healthy proteins. Myr also modulates the aggregation process of protein when added after the onset of aggregation. Circular dichroism (CD) show that Myr delays the structural transition of native α-Syn/E46K/A30P into β-sheets rich fibrillar structures. Myr also disassemble the pre-formed fibrillar structures of α-Syn its mutants. These outcomes offer profound insight into the modulatory mechanism of aggregation of α-Syn, E46K and A30P by Myr, thereby suggesting its potential role in designing combination therapies against protein fibrillation related disorders.

Keywords:  Inhibition; Isothermal titration calorimetry; Protein aggregation

DOI:  https://doi.org/10.1016/j.abb.2025.110470
Sci Rep. 2025 May 23. 15(1): 17879

Epigallocatechin-3-gallate binds tandem RNA recognition motifs of TDP-43 and inhibits its aggregation.

Maria Agnese Morando, Vito D'Alessandro, Angelo Spinello, Martina Sollazzo, Elisa Monaca, Raffaele Sabbatella, Maria Concetta Volpe, Francesca Gervaso, Alessandro Polini, Sarah Mizielinska, Caterina Alfano.

  Transactive response DNA-binding Protein 43 (TDP-43) aggregation is a key pathological feature in Amyotrophic Lateral Sclerosis and related neurodegenerative diseases. This study investigates the inhibitory effects of Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, on TDP-43 aggregation. Using a combination of fluorescence assays, NMR spectroscopy, and computational modeling, we demonstrate that Epigallocatechin-3-gallate significantly delays the nucleation phase of TDP-43 aggregation process, thus inhibiting the formation of TDP-43 aggregates in vitro. Additionally, we proved a direct interaction of the compound with the RNA recognition motifs of TDP-43 and modeled the mechanism of interaction. Our findings reveal that EGCG stabilizes the RRM domains, counteracting aggregation by interfering with the early stages of the amyloidogenic pathway. Furthermore, EGCG's stability under experimental conditions was ensured using reducing agents, highlighting the importance of maintaining its reduced form for reproducible results. These insights underscore the therapeutic potential of EGCG in TDP-43 proteinopathies and provide a foundation for developing targeted treatments for ALS and related disorders.

Keywords:  ALS; EGCG stability; Protein aggregation; Protein-ligand interaction; RNA-binding proteins; TDP-43

DOI:  https://doi.org/10.1038/s41598-025-02035-6
Mol Aspects Med. 2025 May 20. pii: S0098-2997(25)00033-0. [Epub ahead of print]103 101369

Virus-like particles of retroviral origin in protein aggregation and neurodegenerative diseases.

Serena Carra, Balazs Fabian, Hamed Taghavi, Edoardo Milanetti, Valeria Giliberti, Giancarlo Ruocco, Jason Shepherd, Michele Vendruscolo, Monika Fuxreiter.

A wide range of human diseases are associated with protein misfolding and amyloid aggregates. Recent studies suggest that in certain neurological disorders, including Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD) and various tauopathies, protein aggregation may be promoted by virus-like particles (VLPs) formed by endogenous retroviruses (ERVs). The molecular mechanisms by which these VLPs contribute to protein aggregation, however, remain enigmatic. Here, we discuss possible molecular mechanisms of ERV-derived VLPs in the formation and spread of protein aggregates. An intriguing possibility is that liquid-like condensates may facilitate the formation of both protein aggregates and ERV-derived VLPs. We also describe how RNA chaperoning, and the encapsulation and trafficking of misfolded proteins, may contribute to protein homeostasis through the elimination of protein aggregates from cells. Based on these insights, we discuss future potential therapeutic opportunities.

DOI: https://doi.org/10.1016/j.mam.2025.101369
Front Cell Dev Biol. 2025 ;13 1538377

Small HSPs at the crossroad between protein aggregation, autophagy and unconventional secretion: clinical implications and potential therapeutic opportunities in the context of neurodegenerative diseases.

Raffaella Bonavita, Fulvia Vitale, Luigi Vittorio Verdicchio, Sarah V Williams, Maria Gabriella Caporaso, Angeleen Fleming, Maurizio Renna.

  Neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's and Huntington's diseases as well as ataxias and fronto-temporal disorders are all characterized by the progressive accumulation of protein aggregates (amyloids) into inclusions bodies. In addition, recent experimental evidence is challenging the conventional view of the disease by revealing the ability of some of these disease-relevant proteins to be transferred between cells by means of extracellular vesicles (EVs), allowing the mutant protein to seed oligomers involving both the mutant and wild type forms of the protein. Abnormal secretion and levels of EVs are closely related to the pathogenesis of neurodegenerative diseases and contribute to disease progression. Numerous studies have proposed EVs as therapeutic targets or biomarkers for neurodegenerative diseases. In this review, we summarize and discuss the role of small heat shock proteins (sHSPs) and autophagy in cellular quality control and turn-over of the major aggregation-prone proteins associated to neurodegenerative disorders. We also highlight the advanced research progress on mechanisms regulating unconventional secretion, secretory autophagy and EVs biogenesis and their contribution in the pathological processes underlining these diseases. Finally, we outline the latest research on the roles of EVs in neurodegenerative diseases and their potential diagnostic and therapeutic significance for the treatment of these clinically relevant conditions.

Keywords:  autophagy; extracellular vesicles and exosomes; neurodegenerative diseases; protein misfolding; protein oligomerization and aggregation; small heat shock proteins; unconventional protein secretion

DOI:  https://doi.org/10.3389/fcell.2025.1538377
J Colloid Interface Sci. 2025 May 17. pii: S0021-9797(25)01307-4. [Epub ahead of print]697 137916

Regulating aggregation of an intrinsically disordered chaperone-like casein.

Jaspreet Kaur, Mily Bhattacharya.

  Protein aggregation involving the conversion of soluble protein monomers into insoluble aggregates is prevalent in human diseases, food processing, food formulations, biotechnology-based therapeutics, etc. Molecular chaperones are typically globular proteins that regulate protein folding and aggregation. However, a unique chaperone-like milk protein namely, β-casein, is intrinsically disordered and prone to aggregation under physiological conditions. To regulate protein aggregation, there is a pressing need to devise strategic interventions that require a detailed understanding of the protein conformational changes during self-association. Here, we show that sodium chloride (NaCl) can modulate calcium ions (Ca2+)-induced spontaneous aggregation of β-casein under physiological conditions. Using fluorescence and Raman spectroscopy coupled with light scattering and transmission electron microscopy, we delineate the structural attributes of β-casein during Ca2+-mediated self-association. Our findings reveal that the binding of divalent Ca2+ to five phosphorylated serine residues (calcium phosphate binding-short linear sequence motif; CaP-SLiM), located within the N-terminal-domain of β-casein, is an obligatory prerequisite. This binding event subsequently triggers the formation of inter-casein bridges that facilitate multivalent interactions between the hydrophilic, disordered β-caseins, driving the self-assembly wherein hydrophobic interactions are insignificant compared to β-casein-CaCl2 interactions. Further, the Ca2+-induced β-casein aggregation is accompanied by a disorder-to-order transition resulting in non-amyloid, spherical aggregates. We also demonstrate that NaCl influences the aggregation propensity of β-casein by electrostatically screening the polypeptide and leads to the formation of aggregation-incompetent oligomers by abolishing the binding of Ca2+ to β-casein and the subsequent formation of inter-casein linkages, thus, affirming the pivotal role of CaP-SLiMs and multivalency during β-casein aggregation.

Keywords:  Casein; Protein aggregation; Protein-protein interactions; Self-assembly; Soft colloids

DOI:  https://doi.org/10.1016/j.jcis.2025.137916
J Mol Biol. 2025 May 16. pii: S0022-2836(25)00285-2. [Epub ahead of print] 169219

Autophagy dysfunction and neurodegeneration: Where does it go wrong?

Daphne Oettinger, Ai Yamamoto.

  An infamous hallmark of neurodegenerative diseases is the accumulation of misfolded or unfolded proteins forming inclusions in the brain. The accumulation of these abnormal structures is a mysterious one, given that cells devote significant resources to integrate complementary pathways to ensure proteome integrity and proper protein folding. Aberrantly folded protein species are rapidly targeted for disposal by the ubiquitin-proteasome system (UPS), and even if this should fail, and the species accumulates, the cell can also rely on the lysosome-mediated degradation pathways of autophagy. Despite the many safeguards in place, failure to maintain protein homeostasis commonly occurs during, or preceding, the onset of disease. Over the last decade and a half, studies suggest that the failure of autophagy may explain the disruption in protein homeostasis observed in disease. In this review, we will examine how the highly complex cells of the brain can become vulnerable to failure of aggregate clearance at specific points during the processive pathway of autophagy, contributing to aggregate accumulation in brains with neurodegenerative disease.

Keywords:  Neurodegeneration; Protein aggregation; glia; neurons; protein homeostasis

DOI:  https://doi.org/10.1016/j.jmb.2025.169219
Autophagy Rep. 2024 ;3(1): 2314361

Alpha-synuclein aggregates trigger cardiolipin externalization and mitophagy.

Rebeca Martín-Jiménez, Olivier Lurette, Etienne Hebert-Chatelain.

  Accumulation of Lewy bodies in dopaminergic neurons is associated to Parkinson disease (PD). The main component of Lewy bodies appears to be aggregates of alpha-synuclein (α-syn). Several mutations of the gene encoding this protein promote its aggregation. Thus, clustering of α-syn is considered a central event in the onset of PD. An old theory also postulates that mitochondrial dysfunction represents another cause of PD pathogenesis. However, the impact of α-syn aggregates on mitochondria remains poorly understood considering the technical difficulties to discriminate between the different forms of α-syn. In this punctum, we describe our recent work in which we used a newly developed optogenetic tool to control the aggregation of α-syn and examine the impact on mitochondria. This work revealed that α-syn aggregates dynamically interact with mitochondria, triggering their depolarization and leading to cardiolipin translocation to the surface of mitochondria and mitophagy. Abbreviations: α-syn: alpha-synuclein; BNIP3L: BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like; FUNDC1: FUN14 domain-containing protein 1; IMM: inner mitochondrial membrane; LIPA: light-induced protein aggregation; OMM: outer mitochondrial membrane; PD: Parkinson disease; SNc: substantia nigra par compacta.

Keywords:  Lewy bodies; PLSCR3; mitochondrial fission; mitochondrial membrane potential; parkinson disease; selective autophagy; ubiquitin

DOI:  https://doi.org/10.1080/27694127.2024.2314361
ACS Sens. 2025 May 23.

Endoplasmic Reticulum Stress Induces Liquid-Liquid Phase Separation of GRP78 and Modulates Protein Aggregation Dynamics.

Jiaqi Li, Xiangyu Zi, Jiabao Fang, Min Liang, Minzi Ju, Zhenglong Sun, Baoxing Shen, Xin Zhang.

  Abnormal protein aggregation is a hallmark of neurodegenerative diseases, disrupting cellular homeostasis. Glucose-regulated protein 78 (GRP78), a key endoplasmic reticulum (ER) chaperone, plays a crucial role in protein folding and the ER stress response. Recent studies suggest that GRP78 undergoes liquid-liquid phase separation (LLPS) to form dynamic condensates; however, its functional implications under pathological conditions remain unclear. In this study, we designed and synthesized two fluorescent probes (ER-Pro and Agg-Pro) for specifically labeling GRP78 and monitoring microenvironmental polarity changes during protein phase transition. By integrating fluorescence lifetime imaging microscopy and confocal microscopy, we demonstrated that GRP78 undergoes LLPS under ER stress and recruits the amyotrophic lateral sclerosis-associated mutant protein SOD1(A4V), influencing its aggregation dynamics. Further investigations revealed that SOD1(A4V) aggregation is accompanied by local polarity changes, highlighting a potential role for GRP78 LLPS in protein quality control. Our findings provide new insights into ER homeostasis regulation and the pathogenesis of neurodegenerative diseases, offering potential strategies for early diagnosis and therapeutic intervention.

Keywords:  endoplasmic reticulum stress; fluorescence lifetime imaging; liquid−liquid phase separation; polarity sensitivity; protein aggregation

DOI:  https://doi.org/10.1021/acssensors.5c00807
Protein Sci. 2025 Jun;34(6): e70162

Inhibition of tau aggregation by the CCT3 and CCT7 apical domains.

Miki Ben-Maimon, Nadav Elad, Segev Naveh-Tassa, Yaakov Levy, Amnon Horovitz.

  The eukaryotic chaperonin containing t-complex polypeptide 1 (CCT/TRiC) is a molecular chaperone that assists protein folding in an ATP-driven manner. It consists of two stacked identical rings that are each made up of eight distinct subunits. Here, we show that the apical domains of subunits CCT3 and CCT7 from humans are strong inhibitors of tau aggregation, which is associated with several neurological disorders such as Alzheimer's and Parkinson's diseases. Kinetic analyses and negative-stain electron microscopy indicate that the mechanism of inhibition of tau aggregation by the apical domains of subunits CCT3 and CCT7 differ. Aggregation of tau alone, or in the presence of the apical domain of subunit CCT7, can be described by a fragmentation model whereas in the presence of the apical domain of subunit CCT3, it fits a saturating elongation and fragmentation mechanism. Coarse-grained molecular dynamics simulations show that tau interacts with different regions in the apical domains of subunits CCT3 and CCT7, in agreement with their different inhibition mechanisms.

Keywords:  Alzheimer's disease; CCT/TRiC; chaperonins; protein aggregation; tau

DOI:  https://doi.org/10.1002/pro.70162
Cell Mol Neurobiol. 2025 May 19. 45(1): 44

Exploring α-Syn's Functions Through Ablation Models: Physiological and Pathological Implications.

Anjali Praveen, Godfried Dougnon, Hideaki Matsui.

  A significant advancement in neurodegenerative research was the discovery that α-synuclein (α-Syn/SNCA) plays a part in the pathophysiology of Parkinson's disease (PD). Decades later, the protein's significant impacts on various brain disorders are still being extensively explored. In disease conditions, α-Syn misfolds and forms abnormal aggregates that accumulate in neurons, thus triggering various organellar dysfunctions and ultimately neurodegeneration. These misfolded forms are highly heterogeneous and vary significantly among different synucleinopathies, such as PD, Multiple System Atrophy, or Dementia with Lewy bodies. Though initially believed to be exclusively localized in the brain, numerous pieces of evidence suggest that α-Syn functions transcend the central nervous system, with roles in peripheral functions, such as modulation of immune responses, hematopoiesis, and gastrointestinal regulation. Here, we aim to provide a detailed compilation of cellular functions and pathological phenotypes that are altered upon attenuation of α-Syn function in vitro and in vivo and explore the effects of SNCA gene silencing in healthy and disease states using cellular and animal models.

Keywords:   SNCA ; α-Syn; Ablation models; Parkinson's disease; Synuclein

DOI:  https://doi.org/10.1007/s10571-025-01560-2