bims-proned 2025-06-15 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–06–15
nineteen papers selected by
Verena Kohler, Umeå University

α-Synuclein Sequences from Long-Lived Animals Display Generally Diminished Aggregation Compared to Shorter-Lived Animals Including Humans.
Rethinking Parkinson's: The role of proteostasis networks and autophagy in disease progression.
Clearance Pathways for α-Synuclein in Parkinson's Disease.
Therapeutic Potential of Flavonoids Against α-Synuclein Aggregation in Parkinson's Disease: Integrative In Silico and In Vitro Analysis''.
Studies on curcumin-glucoside in the prevention of alpha-synuclein aggregation.
Decoding crosstalk between neurotransmitters and α-synuclein in Parkinson's disease: pathogenesis and therapeutic implications.
Broken Balance: Emerging Cross-Talk Between Proteostasis and Lipostasis in Neurodegenerative Diseases.
Direct Observation of Secondary Nucleation in Huntingtin Amyloid Formation by High-Speed Atomic Force Microscopy.
Pathological Disulfide bond Crosslinking: Molecular Insights into Amyloidogenesis and Diseases Progression.
A Global Thermodynamic-Kinetic Model Capturing the Hallmarks of Liquid-Liquid Phase Separation and Amyloid Aggregation.
Berberine's paradox in Neurodegeneration: Therapeutic promise and safety challenges in Parkinson's disease.
Protein Pathologies in Oligodendroglia in Neurodegenerative Diseases.
α-Synuclein Pathology in Synucleinopathies: Mechanisms, Biomarkers, and Therapeutic Challenges.
The infectious potential of protein misfolding: insights from cross-over studies of prion diseases and common neurodegenerative disorders.
Anion Binding and Aggregation of N‑Terminal α‑Synuclein Peptides.
Emerging Techniques for the Identification of Traditional Chinese Medicine-Derived Molecules Targeting Parkinson's Disease.
Modeling Protein Aggregation Kinetics from NMR Data.
Limiting TDP-43 aggregation by induced recruitment to PML-NB.
EGFR phosphorylates DNAJB1 to suppress α-synuclein aggregation in Parkinson's disease.

Chembiochem. 2025 Jun 10. e202500340

α-Synuclein Sequences from Long-Lived Animals Display Generally Diminished Aggregation Compared to Shorter-Lived Animals Including Humans.

Gilbert B Ampomah, Eldon R Hard, Matthew Robert Pratt.

  The overall process of protein aggregation from soluble species to amyloid fibrils is toxic to neurons and can propagate along neuronal connections in ways that potentially explain the pathological progression in most neurodegenerative diseases. One of these aggregation-prone proteins is α-synuclein (α-Syn), which forms insoluble protein deposits in Parkinson's disease and other synucleinopathies. The majority of cases of Parkinson's disease occur fairly late in life and even early-onset variants of the disease caused by mutations to α-Syn occur towards the end of the lifespan for prehistoric man. This suggests a lack of evolutionary pressure to prevent protein aggregation in animals with similar or shorter lifespans. However, α-Syn is also found in animals with notably longer lifespans. Here, we tested the aggregation propensity of α-Syn sequences from short- and longer-lived animals at a range of evolutionary distances from humans. We find that in general longer-lived animals display slower α-Syn aggregation kinetics and the formation of smaller and less uniform fibrils. Overall, our data indicate that some evolutionary pressure may have existed for preventing α-Syn aggregation, but that pressure was lost in the more recent branch of shorter-lived animals containing humans.

Keywords:  Synuclein, Aggregation, Amyloid, Evolution

DOI:  https://doi.org/10.1002/cbic.202500340
Mol Cell Neurosci. 2025 Jun 07. pii: S1044-7431(25)00033-8. [Epub ahead of print]134 104023

Rethinking Parkinson's: The role of proteostasis networks and autophagy in disease progression.

Akhil Sharma, Ashi Mannan, Thakur Gurjeet Singh.

  Protein dyshomeostasis is identified as the hallmark of many age-related NDDs including Parkinson's disease (PD). PD is a progressive neurodegenerative disorder (NDD) characterized by the accumulation of misfolded proteins, particularly α-synuclein (α-syn) leading to formation of Lewy bodies and cause degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc). Disruption of the cell's normal protein balance, which occurs when cells experience stress, plays a key role in causing the formation of harmful protein clumps. Functional proteostasis relies on coordinated mechanisms involving posttranslational modifications (PTMs), molecular chaperones, the unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), and the autophagy-lysosome pathway (ALP). These networks maintain proper synthesis, folding, confirmation and degradation of protein such as α-syn protein in PD. These approaches include enhancing lysosomal function, promoting autophagy and modulating the unfolded protein response. Understanding the complex interactions between these pathways is essential for developing effective treatments. This review synthesizes current knowledge of various genes and molecular mechanisms underlying proteostasis disruption in PD and evaluates emerging therapeutic strategies that target multiple genes and pathways simultaneously. The finding highlights the potential of integrated approaches to restore protein homeostasis and prevent neurodegeneration, offering new directions for PD treatment development.

Keywords:  Autophagy-lysosome pathway (ALP); Molecular chaperones; Parkinson's disease (PD); Posttranslational modifications (PTMs); Proteostasis; Ubiquitin-proteasome system (UPS); Unfolded protein response (UPR); α-Synuclein (α-syn)

DOI:  https://doi.org/10.1016/j.mcn.2025.104023
J Neurochem. 2025 Jun;169(6): e70124

Clearance Pathways for α-Synuclein in Parkinson's Disease.

Margaret S Ho.

  Protein aggregation and accumulation are hallmark features of neurodegenerative diseases. In Parkinson's disease, the progressive formation and propagation of α-synuclein aggregates-found in Lewy bodies and Lewy neurites-are closely linked to widespread neuronal dysfunction, dopaminergic neuron loss, and the emergence of both motor and nonmotor symptoms, including anosmia, cognitive decline, and depression. Despite their pathological significance, the mechanisms underlying the formation, spread, and clearance of these aggregates remain incompletely understood. In this review, we examine the cellular and molecular pathways responsible for the elimination of protein aggregates in the diseased brain. We first summarize various experimental models of α-synuclein pathology, followed by a discussion of the degradation mechanisms in neurons and glial cells under pathological conditions. These findings offer new insights into cell type-specific clearance pathways and highlight potential therapeutic targets for mitigating α-synuclein-associated toxicity in Parkinson's disease.

Keywords:  Parkinson's disease; UPS; autophagy; degradation; α‐Synuclein

DOI:  https://doi.org/10.1111/jnc.70124
Eur J Pharmacol. 2025 Jun 07. pii: S0014-2999(25)00583-7. [Epub ahead of print] 177829

Therapeutic Potential of Flavonoids Against α-Synuclein Aggregation in Parkinson's Disease: Integrative In Silico and In Vitro Analysis''.

Fereshteh Ramezani Khorsand, Bahareh Dabirmanesh, Khosro Khajeh.

  Amyloidogenic protein aggregation is the key factor in neurodegenerative diseases. Due to the cost-effectiveness and low side effects, attention to herbal medicines has been recently increased. Flavonoids are a group of plant compounds with high potential for reducing the accumulation of amyloidogenic proteins. This research aims to identify the most effective flavonoids for inhibiting the fibrillation of α-synuclein (α-syn). For this purpose, 98 flavonoids from different databases were selected for analysis. The pharmacokinetic properties of these flavonoids were evaluated using OSIRIS and Swiss-ADME web tools. The interaction of α-syn and flavonoids was investigated in the positions predicted via DoGSiteScorer and CASTp web servers. Subsequently, luteolin and baicalein, the flavonoids with the most negative binding energy and interaction with the amino acids of α-syn amyloidogenic regions, were selected for further in vitro studies. In this phase, α-syn was incubated under fibrillation conditions in the presence and absence of flavonoid treatment. Results from the thioflavin T (ThT) fluorescence assay, atomic force microscopy (AFM), and proteinase K (PK) enzymatic digestion assay showed that baicalein and luteolin significantly inhibited α-syn fibril formation. Fourier transform infrared spectroscopy (FTIR) demonstrated a decrease in β-sheet content and confirmed the inhibitory effect of baicalein and luteolin. In addition, cell culture analysis also showed that luteolin could increase the viability of SH-SY5Y cells exposed to α-syn fibrils by destabilizing toxic fibrils and converting them into non-toxic amorphous aggregates. These findings can be useful to develop flavonoid-based therapeutic strategies for synucleinopathies, such as Parkinson's disease (PD).

Keywords:  Anti-fibrillation; Flavonoid; Molecular docking; Neurodegenerative disease; α-synuclein

DOI:  https://doi.org/10.1016/j.ejphar.2025.177829
J Alzheimers Dis Rep. 2025 Jan-Dec;9:9 25424823251347260

Studies on curcumin-glucoside in the prevention of alpha-synuclein aggregation.

Lakshmi Sowmya Emani, Jayanth K Rao, Jagadeesha Kumar Dasappa, Marisín Pecchio, Johant Lakey-Beitia, Hansapani Rodriguez, Jessica Cruz-Mora, Priya Narayan, Nikhilesh Anand, Govindaraju Mullur, Rajanna Ajumeera, Bharathi S Gadad, Jagannatha Rao Kosagisharaf.

   Background: α-synuclein (α-syn) deposition in the mid-brain region is one of the hallmark pathologies of Parkinson's disease (PD). The key steps involve the transformation of α-synuclein into a toxic oligomer and insoluble fibrillar aggregates.
Objective: To understand the role of curcumin-glucoside in the prevention of α-syn aggregation, a mechanistic approach.
Methods: In the present study, we synthesized a novel molecule, curcumin-glucoside (Curc-gluc), to improve the water solubility and partition coefficient, making the molecule with high bioavailability. The present study is focused on understanding the α-syn aggregation kinetics in the presence and absence of Curc-gluc, curcumin (Cur), copper (Cu), and iron (Fe) through Thioflavin T analysis, circular dichroism (CD), mathematical approach by self-association kinetics, and molecular docking models.
Results: The results indicated that Curc-gluc potentially prevented synuclein aggregation compared to Curc alone and inhibited Cu and Fe-induced synuclein aggregation. CD studies indicated that Curc-gluc favored α-helix formation. The docking studies indicated that Curc-gluc derivatives interacted with various chains of α-syn fibrils, namely G-chain, A-chain, I-Chain, and E-chain and the Pi-Pi interaction indicate that, Curc-gluc shows the most favorable binding affinity with the α-syn fibrils with 60.7222 kcal/mol of -CDOCKER_ ENERGY and 89.6516 kcal/mol of -CDOCKER INTERACTION_ ENERGY. The Absorption, Distribution, Metabolism, Excretion (ADME) analysis indicated that Curc-mono and di-gluc have the highest solubility, bioavailability, and tissue distribution compared to Curc alone.
Conclusions: The studies indicated that Curc-gluc prevented α-syn aggregation by favoring α-helix, binding to α-syn, and preventing aggregation, and had high bioavailability.

Keywords:  ADMET; Alzheimer's disease; Parkinson's disease; aggregation; circular dichroism; curcumin; curcumin glucoside; docking models; future drug; pharmacokinetics; synuclein

DOI:  https://doi.org/10.1177/25424823251347260
Ther Adv Neurol Disord. 2025 ;18 17562864251339895

Decoding crosstalk between neurotransmitters and α-synuclein in Parkinson's disease: pathogenesis and therapeutic implications.

Lihua Guan, Liling Lin, Chaochao Ma, Ling Qiu.

  Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by progressive worsening of motor symptoms. The primary pathological hallmark of PD is the degeneration of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies, which are primarily composed of α-synuclein (α-syn) aggregates. Both α-syn and various neurotransmitters, including catecholamines (catechols), play crucial roles in the pathogenesis of PD, although the precise pathogenic mechanisms remain incompletely understood. The crosstalk between neurotransmitters and α-syn is intricate and multifaceted. Pathological α-syn disrupted neurotransmitters' homeostasis by impairing release and reuptake of neurotransmitters, with specific modulation of catecholaminergic and glutamatergic systems. Conversely, neurotransmitters, especially catechols, covalently modify α-syn. Such modifications significantly influence α-syn aggregation dynamics and alter its neurotoxic properties. However, determining whether these interactions induce synergistic toxicity or confer neuroprotection remains controversial. Emerging evidence suggests other neurotransmitters like serotonin and γ-aminobutyric acid may also modulate α-syn aggregation and PD progression, though their roles require further investigation. Understanding these interactions is crucial for developing novel diagnostic and multi-target therapeutic strategies.

Keywords:  Parkinson’s disease; catecholamine; interaction; neurotransmitters; α-synuclein

DOI:  https://doi.org/10.1177/17562864251339895
Cells. 2025 Jun 04. pii: 845. [Epub ahead of print]14(11):

Broken Balance: Emerging Cross-Talk Between Proteostasis and Lipostasis in Neurodegenerative Diseases.

Jessica Tittelmeier, Carmen Nussbaum-Krammer.

  Neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, are characterized by progressive neuronal loss, leading to cognitive and motor impairments. Although these diseases have distinct clinical manifestations, they share pathological hallmarks such as protein aggregation and lysosomal dysfunction. The lysosome plays a vital role in maintaining cellular homeostasis by mediating the degradation and recycling of proteins, lipids, and other macromolecules. As such, it serves as a central hub for both proteostasis and lipostasis. This review outlines genetic and mechanistic parallels between rare lysosomal lipid storage diseases, such as Gaucher disease and Niemann-Pick disease, and more prevalent neurodegenerative diseases. We discuss how impaired lysosomal sphingolipid metabolism compromises lysosomal integrity, disrupts proteostasis, and contributes to neurodegeneration. Furthermore, we describe how age-related decline in lysosomal function may similarly drive neurodegeneration in the absence of overt genetic mutations. Taken together, this review highlights the lysosome as a central integrator of protein and lipid homeostasis and emphasizes the bidirectional relationship between lipostasis and proteostasis, whereby disruption of one adversely affects the other in the pathogenesis of multiple neurodegenerative diseases.

Keywords:  lipostasis; lysosomal lipid storage diseases; lysosome; neurodegenerative diseases; prion-like propagation; proteostasis; sphingolipidoses

DOI:  https://doi.org/10.3390/cells14110845
J Am Chem Soc. 2025 Jun 12.

Direct Observation of Secondary Nucleation in Huntingtin Amyloid Formation by High-Speed Atomic Force Microscopy.

Chris van Ewijk, Greeshma Jain, Yari K Knelissen, Sourav Maity, Patrick C A van der Wel, Wouter H Roos.

Amyloid fibril formation is a hallmark of various neurodegenerative diseases such as Huntington's (HD), Alzheimer's, and Parkinson's disease. The protein aggregation process involves slow nucleation events followed by rapid growth and elongation of formed fibrils. Understanding the pathways of amyloid formation is key to development of novel therapeutic agents that can interfere with the pathogenic protein misfolding events. Recent studies of aggregation by polypeptides from Alzheimer's and Huntington's disease have identified the importance of a poorly understood secondary nucleation process that may even be the dominant source of protein aggregate formation. Here, we focus on the polyglutamine-expansion disorder HD and employ mechanistic and structural studies to study different aspects of secondary nucleation in the aggregation of huntingtin Exon 1 (HttEx1). Notably, we apply high-speed atomic force microscopy (HS-AFM) to directly observe the process on the single-particle level and in real time. Our observations show unique features of the amyloid formation dynamics in real time, including secondary nucleation, elongation, and the formation of large bundles of fibrils as a result of nucleated branching. We examine the role of HttEx1 flanking segments during the aggregation process, revealing that the N-terminal HttNT segment exhibits a clear primary nucleation-aggregation-enhancing ability; however, it does not seem to induce or affect the secondary nucleation process. The obtained results illuminate the complex aggregation process of HttEx1 and have implications for attempts to inhibit or modulate it for therapeutic purposes.

DOI: https://doi.org/10.1021/jacs.5c05571
Chembiochem. 2025 Jun 10. e202500316

Pathological Disulfide bond Crosslinking: Molecular Insights into Amyloidogenesis and Diseases Progression.

Yun Kyung Kim, Dong Min Kang, Nataliia Lukianenko, Ja-Hyun Baik, Sungsu Lim.

  Amyloidogenesis is a complex process in which normally soluble proteins misfold and assemble into β-sheet-rich aggregates known as amyloid fibrils. This pathological process is implicated in a broad range of diseases, including neurodegenerative disorders and systemic amyloidosis. Recent studies indicate that disulfide-crosslinking plays a central role in promoting protein aggregation by stabilizing misfolded intermediates. This review highlights the cellular pathways leading to abnormal disulfide bond formation and examines their impact on disease progression. Additionally, we discuss how disulfide-crosslinked oligomeric species resist degradation, overwhelm proteostasis systems, and serve as precursors for amyloid fibrils. By understanding the role of disulfide crosslinks in protein aggregation, we gain insights into amyloid pathogenesis and identify potential therapeutic targets for intervention.

Keywords:  Amyloidogenic protein; Disulfide-crosslinking; Oxidation; Protein folding; aggregation

DOI:  https://doi.org/10.1002/cbic.202500316
bioRxiv. 2025 May 27. pii: 2025.05.23.655849. [Epub ahead of print]

A Global Thermodynamic-Kinetic Model Capturing the Hallmarks of Liquid-Liquid Phase Separation and Amyloid Aggregation.

Kamal Bhandari, Yunxiang Sun, Huayuan Tang, Pu Chu Ke, Feng Ding.

Aberrant aggregation of proteins into amyloid fibrils is associated with numerous neurodegenerative, systemic and metabolic diseases. Amyloidogenic proteins undergo spontaneous liquid-liquid phase separation (LLPS), rapidly forming protein-rich condensates prior to fibrillization. However, the exact effects of LLPS on amyloid aggregation remain unclear as contrasting fibrillization-promotion, inhibition and even biphasic effects have been reported in the literature. In this study, we integrate LLPS-induced heterogeneity of protein concentrations into a thermodynamic-kinetic model of amyloid aggregation. We adopt the phase transition theory and introduce protein condensates as an additional protein state alongside non-interacting monomers, oligomers and fibrils. Oligomerization and fibrillization can occur both in the protein-rich condensates and the protein-poor solution. This model allows us to derive the time evolution of different states - monomers, condensates, oligomers, and fibrils - spanning a wide range of concentrations, and determine how model parameters related to LLPS, fibrillization, and oligomerization influence fibrillization kinetics. Using this global model, we resolve the seemingly contradictory effects of LLPS on fibrillization. We expect the developed thermodynamic-kinetic model of LLPS, and amyloid aggregation will help advance our understanding, modulation, and mitigation of pathological aggregation processes in amyloid diseases.
TOC:

DOI: https://doi.org/10.1101/2025.05.23.655849
Neuropharmacology. 2025 Jun 06. pii: S0028-3908(25)00261-8. [Epub ahead of print]278 110555

Berberine's paradox in Neurodegeneration: Therapeutic promise and safety challenges in Parkinson's disease.

Sultan M Alshahrani, Hayder M Al-Kuraishy, Ali I Al-Gareeb, Ali K Albuhadily, Mohamed N Fawzy, Sultan F Kadasah, Mubarak Alruwaili, Marios Papadakis, Athanasios Alexiou, Gaber El-Saber Batiha.

  Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). α-Synuclein (α-Syn) is a key protein implicated in PD pathogenesis, with its structural and biophysical properties widely investigated due to their role in disease mechanisms. The presence of Lewy bodies and Lewy neurites, pathological hallmarks of PD primarily composed of aggregated α-Syn, further underscores its critical involvement. This correlation has led to the hypothesis that α-Syn aggregation actively contributes to PD development. Recent studies have implicated oligomers formed during the initial phases of protein aggregation as the primary neurotoxic agents driving cellular degeneration in PD. This pathological process worsens mitochondrial dysfunction, oxidative stress, and microglial activation, ultimately contributing to SNpc degeneration and PD progression. Currently, available PD medications only provide symptomatic relief and do not address underlying neuropathological mechanisms such as oxidative stress, mitochondrial impairment, α-syn aggregation, or SNpc degeneration. Moreover, long-term use of anti-PD drugs like L-DOPA can lead to motor complications and systemic side effects. As a result, repurposing traditional herbal medicines with antioxidant and anti-inflammatory properties presents a promising therapeutic approach. Studies suggest that berberine (BBR) may mitigate PD-related neuropathology. However, the exact mechanisms by which BBR exerts its neuroprotective effects remain unclear. This review explores the potential molecular pathways through which BBR could alleviate PD pathology.

Keywords:  Alpha synuclein; Berberine; Endoplasmic reticulum; Neurodegenerative disease; Oxidative stress; Parkinson disease

DOI:  https://doi.org/10.1016/j.neuropharm.2025.110555
Adv Neurobiol. 2025 ;43 407-432

Protein Pathologies in Oligodendroglia in Neurodegenerative Diseases.

Shelley L Forrest, Gabor G Kovacs.

  Neurodegenerative diseases are clinically, pathologically and genetically heterogeneous disorders characterised by progressive dysfunction and neuronal loss and the deposition of disease-specific proteinaceous aggregates in neurons and/or glia, showing a hierarchical involvement of brain regions. Research into disease mechanisms underlying neurodegenerative disorders has focused on the proteinaceous neuronal aggregates in vulnerable brain regions leading to neuronal dysfunction and degeneration and onset of clinical symptoms. However, emerging evidence highlights the importance of glia, including oligodendroglia, in the pathogenesis of neurodegenerative diseases, which have been underappreciated and frequently considered secondary to neuronal involvement. Pathologically altered proteins depositing in oligodendroglia comprise phosphorylated tau, α-synuclein, transactive response DNA-binding protein-43 (TDP-43) and occasionally FET/FUS. However, only primary oligodendroglial tau and α-synuclein deposits are considered for neuropathological diagnosis and classification of some tauopathies and synucleinopathies, respectively. Oligodendroglial tau pathology is also seen in ageing-related tau oligodendrogliopathy (ARTOG). This chapter provides an overview of neurodegenerative proteinopathies and protein pathologies affecting oligodendroglia.

Keywords:  Neurodegenerative disease; Oligodendroglia; TDP-43; Tau; α-Synuclein

DOI:  https://doi.org/10.1007/978-3-031-87919-7_14
Int J Mol Sci. 2025 Jun 04. pii: 5405. [Epub ahead of print]26(11):

α-Synuclein Pathology in Synucleinopathies: Mechanisms, Biomarkers, and Therapeutic Challenges.

Oscar Arias-Carrión, Magdalena Guerra-Crespo, Francisco J Padilla-Godínez, Luis O Soto-Rojas, Elías Manjarrez.

  Parkinson's disease and related synucleinopathies, including dementia with Lewy bodies and multiple system atrophy, are characterised by the pathological aggregation of the α-synuclein (aSyn) protein in neuronal and glial cells, leading to cellular dysfunction and neurodegeneration. This review synthesizes knowledge of aSyn biology, including its structure, aggregation mechanisms, cellular interactions, and systemic influences. We highlight the structural diversity of aSyn aggregates, ranging from oligomers to fibrils, their strain-like properties, and their prion-like propagation. While the role of prion-like mechanisms in disease progression remains a topic of ongoing debate, these processes may contribute to the clinical heterogeneity of synucleinopathies. Dysregulation of protein clearance pathways, including chaperone-mediated autophagy and the ubiquitin-proteasome system, exacerbates aSyn accumulation, while post-translational modifications influence its toxicity and aggregation propensity. Emerging evidence suggests that immune responses and alterations in the gut microbiome are key modulators of aSyn pathology, linking peripheral processes-particularly those of intestinal origin-to central neurodegeneration. Advances in biomarker development, such as cerebrospinal fluid assays, post-translationally modified aSyn, and real-time quaking-induced conversion technology, hold promise for early diagnosis and disease monitoring. Furthermore, positron emission tomography imaging and conformation-specific antibodies offer innovative tools for visualising and targeting aSyn pathology in vivo. Despite significant progress, challenges remain in accurately modelling human synucleinopathies, as existing animal and cellular models capture only specific aspects of the disease. This review underscores the need for more reliable aSyn biomarkers to facilitate the development of effective treatments. Achieving this goal requires an interdisciplinary approach integrating genetic, epigenetic, and environmental insights.

Keywords:  Parkinson’s disease; alpha-synuclein; biomarkers; neurodegeneration; protein aggregation; synucleinopathies

DOI:  https://doi.org/10.3390/ijms26115405
Microb Pathog. 2025 Jun 04. pii: S0882-4010(25)00514-5. [Epub ahead of print] 107789

The infectious potential of protein misfolding: insights from cross-over studies of prion diseases and common neurodegenerative disorders.

Lan Deng, Yuanyuan Li, Ailong Sha.

  In recent years, important progress has been made in the study of the pathogenesis of neurodegenerative diseases, especially the role of protein misfolding and aberrant aggregation in the development of diseases has attracted much attention. As a class of zoonotic infectious neurodegenerative diseases caused by prion protein misfolding and aggregation, prion diseases, with their unique transmission characteristics, have provided important insights for the study of other neurodegenerative diseases. A growing body of research has shown that similar abnormal protein aggregation phenomena occur in common neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). These misfolded proteins exhibit striking similarities to prions in terms of seeding capacity, cytotoxicity, and propagation properties. Further investigation into the prion-like behavior of these aberrant proteins in neurodegenerative diseases can offer new directions for diagnosis and treatment. Recent studies have demonstrated that AD can be transmitted through medical routes, which warns us that neurodegenerative diseases are potentially infectious and deserve further attention and research. This article systematically reviews the pathological features and transmission mechanisms of abnormal proteins in prion diseases and other neurodegenerative disorders, aiming to provide a new perspective for the prevention and treatment of these diseases. Moreover, this research holds significant implications for public health and clinical practice. By revealing the potential transmissibility of neurodegenerative diseases, it can help improve medical protocols and reduce the risk of iatrogenic transmission.

Keywords:  Abnormal protein; Neurodegenerative diseases; Prion; Protein-based viroids

DOI:  https://doi.org/10.1016/j.micpath.2025.107789
ACS Omega. 2025 Jun 03. 10(21): 22216-22223

Anion Binding and Aggregation of N‑Terminal α‑Synuclein Peptides.

Ruiqing Wang, Busayo D Alagbe, Henry S Ashbaugh, Bruce C Gibb.

α-Synuclein (α-Syn) is linked to the pathogenesis of Parkinson's disease by its misfolding, aggregation, and accumulation in Lewy bodies, the characteristic amyloids of Parkinson's. N-terminal binding to phospholipid membranes and the resulting random-coil to helical transition are key to the aggregation of α-Syn. However, despite the recognized affinity for the N-terminal domain for phospholipids, the anion affinity for this region has not been comprehensively examined. To probe the effects of monovalent anion binding to the N-terminus, we report here on studies with the 15-mer N-terminal peptide of α-Syn and two mutants in which all three lysines of the wild-type sequence are replaced with either arginine or histidine (1MDVFMXGLSXAXEGV15; X = K, R, or H). Our studies reveal that charge-diffuse anions have a measurable affinity, binding weakly to the midsection of the sequences. However, binding does not induce significant long-range ordering. Nevertheless, MD simulations do reveal a compaction of the peptides in the presence of ClO4 -, supporting the conclusion that anion binding screens the positively charged residues, reducing the effective net positive charge of the peptide and inducing aggregation. Aggregation studies revealed that this reverse Hofmeister effect correlates with anion affinity and that at intermediate salt concentrations or low pH, aggregation follows the Finke-Watzky model. Our findings suggest that changes in simple salt concentrations are unlikely to affect the structure of the N-terminal region of α-Syn and highlight that multipoint interactions between polyanionic phospholipid membranes are a necessary requirement for the random-coil to helical transition observed in the wild type.

DOI: https://doi.org/10.1021/acsomega.5c02618
ACS Chem Neurosci. 2025 Jun 12.

Emerging Techniques for the Identification of Traditional Chinese Medicine-Derived Molecules Targeting Parkinson's Disease.

Yanzhuo Jin, Yurun Yang, Yiran Sun, George D Mellick, Yuanjun Sun, Mingming Xu.

  Parkinson's disease is a neurodegenerative disorder marked by the aggregation of α-synuclein and substantial loss of dopaminergic neurons. While numerous neuroprotective molecules targeting Parkinson's disease have been identified, challenges remain in optimizing the specificity, selectivity, and efficiency of these molecules. Traditional Chinese medicine has emerged as a bountiful source of natural compounds with diverse pharmacological activities, including inhibition of apoptosis or neuroinflammation, modulation of α-synuclein aggregation and clearance of α-synuclein aggregates. This review provides a comparative analysis of representative molecules derived from traditional Chinese medicine that have shown promise in advancing Parkinson's disease treatment, including tanshinones, paeoniflorin, and ginsenosides. Moreover, the review highlights the role of leading-edge analytical techniques, particularly mass spectrometry and magnetic beads, in identifying and characterizing bioactive compounds, streamlining the process of molecule screening, and offering a more efficient approach for drug discovery. By integrating traditional herbal knowledge with modern scientific techniques, this review seeks to offer researchers constructive information about the development of novel molecules with potential for Parkinson's disease treatment.

Keywords:  Parkinson’s disease; magnetic beads; mass spectrometry; traditional Chinese medicine; α-synuclein

DOI:  https://doi.org/10.1021/acschemneuro.5c00127
J Mol Biol. 2025 Jun 09. pii: S0022-2836(25)00335-3. [Epub ahead of print] 169269

Modeling Protein Aggregation Kinetics from NMR Data.

Vitali Tugarinov, Francesco Torricella, Shreya Ghosh, G Marius Clore.

  We provide an overview of the practical aspects of using NMR spectroscopy to follow the time course of protein fibril formation (aggregation) and quantitatively model the kinetics of aggregation processes. Following a brief survey of the theoretical foundations of the kinetics of protein aggregation and its inhibition, the modeling of aggregation kinetics, from data acquired by a series of fast two-dimensional 1H-15N correlation NMR spectra, is described. Examples are drawn from our recent NMR-based studies of (1) the aggregation kinetics of a pathogenic huntingtin exon-1 protein whose fibrillization in neurons is responsible for Huntington's disease, and (2) the kinetics of amyloid β42 fibril formation and the mechanism of its inhibition by the chaperone Hsp104.

Keywords:  Huntington’s disease; NMR fast acquisition methods; NMR spin relaxation; chemical exchange; protein aggregation kinetics; β-amyloid fibril formation

DOI:  https://doi.org/10.1016/j.jmb.2025.169269
Trends Pharmacol Sci. 2025 Jun 05. pii: S0165-6147(25)00102-6. [Epub ahead of print]

Limiting TDP-43 aggregation by induced recruitment to PML-NB.

Chien-Han Kao, Ruey-Hwa Chen.

  TAR DNA binding protein 43 kD (TDP-43) aggregation is associated with several neurodegenerative diseases and limiting TDP-43 aggregates could offer therapeutic benefit. Recently, Wagner et al. utilized the induced proximity to PML for enhancing TDP-43 solubility under stress. Mechanistically, this strategy triggers a SUMOylation-ubiquitylation cascade on TDP-43 and the compartmentalization of TDP-43 to the promyelocytic leukemia-nuclear bodies (PML-NBs).

Keywords:  SUMO-primed ubiquitylation; TDP-43 proteinopathy

DOI:  https://doi.org/10.1016/j.tips.2025.05.012
NPJ Parkinsons Dis. 2025 Jun 07. 11(1): 157

EGFR phosphorylates DNAJB1 to suppress α-synuclein aggregation in Parkinson's disease.

Yun-Yu Huang, Sue-Jane Lin, Wei-Yu Chiang, Yuan-Teng Chang, Chan-Chih Yang, Chia-Yu Liao, Ya-Lan Chang, Chin-Hsien Lin, Shu-Chun Teng.

Parkinson's disease (PD), characterized by α-synuclein accumulation in dopaminergic neurons, is a common neurodegenerative disorder. Recent findings highlight DNAJB1 as a crucial factor in the disaggregation of α-synuclein fibrils in vitro, yet the underlying mechanisms and regulatory processes in neuronal cells remain largely undefined. This study reveals that DNAJB1 facilitates the clearance of α-synuclein via the Hsp70 chaperone system. Phosphorylation of DNAJB1 at tyrosine 5 by the epidermal growth factor receptor (EGFR) is essential for mitigating α-synuclein aggregation, enhancing its interaction with Hsp70. Dysregulation of this pathway disrupts α-synuclein delivery to Hsp70, worsening aggregation in neuronal cells. Analysis of human brain lysates from individuals with PD and unaffected controls showed reduced levels of EGFR and DNAJB1, with an increase in phosphorylated DNAJB1 at Y5. These findings elucidate mechanisms in PD pathology and suggest DNAJB1 as a promising candidate for targeted therapeutic strategies.

DOI: https://doi.org/10.1038/s41531-025-01006-y