bims-proned 2025-03-02 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–03–02
seventeen papers selected by
Verena Kohler, Umeå University

Small Heat Shock Proteins: Protein Aggregation Amelioration and Neuro- and Age-Protective Roles.
Structural basis of a distinct α-synuclein strain that promotes tau inclusion in neurons.
Off-pathway oligomers of α-synuclein and Aβ inhibit secondary nucleation of α-synuclein amyloid fibrils.
Mechanisms of ubiquitin-independent proteasomal degradation and their roles in age-related neurodegenerative disease.
Expanding our understanding of synucleinopathies: proteinopathy, proteinopenia, and lipidopathy.
TDP-43 as a potential retinal biomarker for neurodegenerative diseases.
TDP-43 Aggregate Seeding Impairs Autoregulation and Causes TDP-43 Dysfunction.
GDNF reduces fibril-induced early-stage alpha-synuclein pathology after delivery of 20S proteasome inhibitor lactacystin.
Balancing act: lipid-to-protein ratios steer the aggregation fate of α-synuclein.
Evaluation of the Ability of Wasp Venom Bioinspired Peptides (Fraternine-10 and Octovespin) in the Disaggregation and Anti-Aggregation of Amyloid-β Fibrils.
Kinetic Steering of Amyloid Formation and Polymorphism by Canagliflozin, a Type-2 Diabetes Drug.
Intact microdissection of stellate ganglia in a Parkinson's disease model reveals aggregation of mutant human α-synuclein in their cell bodies.
α-Synuclein Degradation in Brain Pericytes Is Mediated via Akt, ERK, and p38 MAPK Signaling Pathways.
Transition-State-Dependent Spontaneous Generation of Reactive Oxygen Species by Aβ Assemblies Encodes a Self-Regulated Positive Feedback Loop for Aggregate Formation.
The therapeutic potential of (R)-carvedilol in Huntington's disease through enhancement of autophagy-lysosomal pathway via GSK-3β inhibition.
Edaravone mitigates TDP-43 mislocalization in human amyotrophic lateral sclerosis neurons with potential implication of the SIRT1-XBP1 pathway.
α-Synuclein Iron-Responsive-Element RNA and Iron Regulatory Protein Affinity Is Specifically Reduced by Iron in Parkinson's Disease.

Int J Mol Sci. 2025 Feb 11. pii: 1525. [Epub ahead of print]26(4):

Small Heat Shock Proteins: Protein Aggregation Amelioration and Neuro- and Age-Protective Roles.

Tahani H Albinhassan, Bothina Mohammed Alharbi, Entissar S AlSuhaibani, Sameer Mohammad, Shuja Shafi Malik.

  Protein misfolding, aggregation, and aberrant aggregate accumulation play a central role in neurodegenerative disease progression. The proteotoxic factors also govern the aging process to a large extent. Molecular chaperones modulate proteostasis and thereby impact aberrant-protein-induced proteotoxicity. These chaperones have a diverse functional spectrum, including nascent protein folding, misfolded protein sequestration, refolding, or degradation. Small heat shock proteins (sHsps) possess an ATP-independent chaperone-like activity that prevents protein aggregation by keeping target proteins in a folding-competent state to be refolded by ATP-dependent chaperones. Due to their near-universal upregulation and presence in sites of proteotoxic stress like diseased brains, sHsps were considered pathological. However, gene knockdown and overexpression studies have established their protective functions. This review provides an updated overview of the sHsp role in protein aggregation amelioration and highlights evidence for sHsp modulation of neurodegenerative disease-related protein aggregation and aging.

Keywords:  aging; amyloid fibrils; neurodegenerative disorders; protein aggregation; protein-folding; proteome; proteostasis; small heat shock proteins

DOI:  https://doi.org/10.3390/ijms26041525
J Biol Chem. 2025 Feb 25. pii: S0021-9258(25)00200-5. [Epub ahead of print] 108351

Structural basis of a distinct α-synuclein strain that promotes tau inclusion in neurons.

Chuanqi Sun, Kang Zhou, Peter DePaola, Cally Li, Virginia M Y Lee, Z Hong Zhou, Chao Peng, Lin Jiang.

Amyloidoses are predominantly associated with the accumulation of persistent aggregates of a particular protein. For example, the protein α-synuclein characteristically aggregates in Parkinson's disease (PD), while amyloid beta and tau deposits are associated with Alzheimer's disease (AD). However, α-synuclein-positive inclusions have been reportedly found in some tauopathies, and vice versa; tau-positive inclusions can be found in synucleinopathies. This suggests that there may be coexistence or cross-talk between these proteinopathies. This coexistence suggests that the simultaneous presence of these misfolded proteins may amplify pathogenic mechanisms. However, the crosstalk between these two types of proteopathies remains poorly understood. We now determine the structure of α-synuclein fibrils that directly promote tau aggregation. Helical cryoEM reconstruction reveals the 2.6 Å structure of a new α-synuclein fibril polymorph we term 'strain B'; its core is unique, incorporating both the N- and C-termini of α-synuclein. The design of peptides meant to inhibit the formation of this structure demonstrates that the C-terminal domain fragment (D105-E115) of α-synuclein is critical for the formation of 'strain B' fibrils and may play a key role in its interaction with tau. We hypothesize that the unique structure of pathological α-synuclein significantly contributes to tau co-aggregation and plays a role in the intricate interactions among Alzheimer's, Parkinson's, and other neurodegenerative diseases. These findings open new avenues for drug targeting, discovery,and improves our understanding of neurodegenerative pathology.

DOI: https://doi.org/10.1016/j.jbc.2025.108351
J Mol Biol. 2025 Feb 25. pii: S0022-2836(25)00114-7. [Epub ahead of print] 169048

Off-pathway oligomers of α-synuclein and Aβ inhibit secondary nucleation of α-synuclein amyloid fibrils.

Marie P Schützmann, Wolfgang Hoyer.

  α-Synuclein (αSyn) is a key culprit in the pathogenesis of synucleinopathies such as Parkinson's Disease (PD), in which it forms not only insoluble aggregates called amyloid fibrils but also smaller, likely more detrimental species termed oligomers. This property is shared with other amyloidogenic proteins such as the Alzheimer's Disease-associated amyloid-β (Aβ). We previously found an intriguing interplay between off-pathway Aβ oligomers and Aβ fibrils, in which the oligomers interfere with fibril formation via inhibition of secondary nucleation by blocking secondary nucleation sites on the fibril surface. Here, using ThT aggregation kinetics and atomic force microscopy (AFM), we tested if the same interplay applies to αSyn fibrils. Both homotypic (i.e. αSyn) and heterotypic (i.e. Aβ) off-pathway oligomers inhibited αSyn aggregation in kinetic assays of secondary nucleation. Initially soluble, kinetically trapped Aβ oligomers co-precipitated with αSyn(1-108) fibrils. The resulting co-assemblies were imaged as clusters of curvilinear oligomers by AFM. The results indicate that off-pathway oligomers have a general tendency to bind amyloid fibril surfaces, also in the absence of sequence homology between fibril and oligomer. The interplay between off-pathway oligomers and amyloid fibrils adds another level of complexity to the homo- and hetero-assembly processes of amyloidogenic proteins.

Keywords:  -synuclein; A; Amyloid Aggregation; Cross-Seeding; Oligomers; Protofibrils

DOI:  https://doi.org/10.1016/j.jmb.2025.169048
Front Cell Dev Biol. 2024 ;12 1531797

Mechanisms of ubiquitin-independent proteasomal degradation and their roles in age-related neurodegenerative disease.

Taylor R Church, Seth S Margolis.

  Neurodegenerative diseases are characterized by the progressive breakdown of neuronal structure and function and the pathological accumulation of misfolded protein aggregates and toxic protein oligomers. A major contributor to the deterioration of neuronal physiology is the disruption of protein catabolic pathways mediated by the proteasome, a large protease complex responsible for most cellular protein degradation. Previously, it was believed that proteolysis by the proteasome required tagging of protein targets with polyubiquitin chains, a pathway called the ubiquitin-proteasome system (UPS). Because of this, most research on proteasomal roles in neurodegeneration has historically focused on the UPS. However, additional ubiquitin-independent pathways and their importance in neurodegeneration are increasingly recognized. In this review, we discuss the range of ubiquitin-independent proteasome pathways, focusing on substrate identification and targeting, regulatory molecules and adaptors, proteasome activators and alternative caps, and diverse proteasome complexes including the 20S proteasome, the neuronal membrane proteasome, the immunoproteasome, extracellular proteasomes, and hybrid proteasomes. These pathways are further discussed in the context of aging, oxidative stress, protein aggregation, and age-associated neurodegenerative diseases, with a special focus on Alzheimer's Disease, Huntington's Disease, and Parkinson's Disease. A mechanistic understanding of ubiquitin-independent proteasome function and regulation in neurodegeneration is critical for the development of therapies to treat these devastating conditions. This review summarizes the current state of ubiquitin-independent proteasome research in neurodegeneration.

Keywords:  Alzheimer's disease; Huntington's disease; Parkinson's disease; neurodegenerative disease; oxidative stress; proteasome; protein degradation; ubiquitin independent

DOI:  https://doi.org/10.3389/fcell.2024.1531797
FEBS J. 2025 Feb 25.

Expanding our understanding of synucleinopathies: proteinopathy, proteinopenia, and lipidopathy.

Manuel Flores-León, Tiago F Outeiro.

  A possible consequence of the process of protein aggregation in neurodegenerative diseases is the depletion of soluble protein species (proteinopenia), which may, at least in some cases, reduce protein function/activity. This concept, which is often overlooked, may play a role in synucleinopathies such as Parkinson's disease (PD), and dementia with Lewy bodies (DLB), where the protein α-synuclein (aSyn) is known to accumulate in insoluble inclusions. aSyn is at the crossroads between cellular proteostasis and lipidostasis networks and, therefore, we must be aware of the complexity we face when we try to understand the molecular basis of synucleinopathies. Importantly, aSyn and β-glucocerebrosidase (GCase), a sphingolipid hydrolase also strongly implicated in PD and DLB, are connected to lipid biology and to protein quality control function. Thus, changes in the normal relationship between these two proteins may shift the balance in the cell and lead to proteinopathy and/or proteinopenia, while also affecting lipidostasis of cells in the brain. Thus, pathological mechanisms that are a consequence of (a) loss-of-function, (b) gain-of-toxic function, and (c) alterations in lipidostasis need to be carefully analyzed and integrated in our study of the molecular underpinnings of neurodegenerative mechanisms. Here, we highlight implications of the depletion of the soluble form of aSyn, and of GCase, and discuss how state-of-the-art 'omics technologies' could be deployed to assist in the clinical assessment of synucleinopathies.

Keywords:  Parkinson's disease; alpha‐synuclein; lipids; protein aggregation; synucleinopathy; transcription

DOI:  https://doi.org/10.1111/febs.70011
Front Neurosci. 2025 ;19 1533045

TDP-43 as a potential retinal biomarker for neurodegenerative diseases.

Margit Glashutter, Printha Wijesinghe, Joanne A Matsubara.

  TDP-43 proteinopathies are a spectrum of neurodegenerative diseases (NDDs) characterized by the pathological cytoplasmic aggregation of the TDP-43 protein. These include amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), and others. TDP-43 in the eye shows promise as a biomarker for these NDDs. Several studies have identified cytoplasmic TDP-43 inclusions in retinal layers of donors with ALS, FTLD, AD, CTE, and other conditions using immunohistochemistry. Our findings suggest that pathological aggregates of TDP-43 in the human retina are most prevalent in FTLD-TDP, ALS, and CTE, suggesting these diseases may provide the most reliable context for studying the potential of TDP-43 as a retinal biomarker. Animal model studies have been pivotal in exploring TDP-43's roles in the retina, including its nuclear and cytoplasmic localization, RNA binding properties, and interactions with other proteins. Despite these advances, more research is needed to develop therapeutic strategies. A major limitation of human autopsy studies is the lack of corresponding brain pathology assessments to confirm TDP-43 proteinopathy diagnosis and staging. Other limitations include small sample sizes, lack of antemortem eye pathology and clinical histories, and limited comparisons across multiple NDDs. Future directions for the TDP-43 as a retinal biomarker for NDDs include retinal tracers, hyperspectral imaging, oculomics, and machine learning development.

Keywords:  TDP-43 proteinopathy; biomarker; brain; eye; neurodegenerative disease; retina

DOI:  https://doi.org/10.3389/fnins.2025.1533045
bioRxiv. 2025 Feb 12. pii: 2025.02.11.637743. [Epub ahead of print]

TDP-43 Aggregate Seeding Impairs Autoregulation and Causes TDP-43 Dysfunction.

Lohany Dias Mamede, Miwei Hu, Amanda R Titus, Jaime Vaquer-Alicea, Rachel L French, Marc I Diamond, Timothy M Miller, Yuna M Ayala.

The aggregation, cellular mislocalization and dysfunction of TDP-43 are hallmarks of multiple neurodegenerative disorders. We find that inducing TDP-43 aggregation through prion-like seeding gradually diminishes normal TDP-43 nuclear localization and function. Aggregate-affected cells show signature features of TDP-43 loss of function, such as DNA damage and dysregulated TDP-43-target expression. We also observe strong activation of TDP-43-controlled cryptic exons in cells, including human neurons treated with proteopathic seeds. Furthermore, aggregate seeding impairs TDP-43 autoregulation, an essential mechanism controlling TDP-43 homeostasis. Interestingly, proteins that normally interact with TDP-43 are not recruited to aggregates, while other factors linked to TDP-43 pathology, including Ataxin 2, specifically colocalize to inclusions and modify seeding-induced aggregation. Our findings indicate that TDP-43 aggregation, mislocalization and loss of function are strongly linked and suggest that disruption of TDP-43 autoregulation establishes a toxic feed-forward mechanism that amplifies aggregation and may be central in mediating this pathological connection.

DOI: https://doi.org/10.1101/2025.02.11.637743
Eur J Pharm Sci. 2025 Feb 21. pii: S0928-0987(25)00047-8. [Epub ahead of print] 107048

GDNF reduces fibril-induced early-stage alpha-synuclein pathology after delivery of 20S proteasome inhibitor lactacystin.

Safak Er, Ilmari Parkkinen, Karolina Trepczyk, Anna Seelbach, Maria Samuela Pasculli, Francesca De Lorenzo, Kelvin Luk, Elzbieta Jankowska, Piotr Chmielarz, Andrii Domanskyi, Mikko Airavaara.

  Failures in protein homeostasis are linked to Parkinson's disease (PD) and other neurodegenerative diseases. Lewy bodies, proteinaceous inclusions rich in phosphorylated alpha-synuclein are a hallmark of PD. Glial cell line-derived neurotrophic factor (GDNF) can eliminate Lewy body-like inclusions in mouse dopamine neurons. This study explores whether GDNF has protective effects against alpha-synuclein protofibril toxicity under proteasome inhibition by lactacystin, both in vitro and in vivo. GDNF did not shield midbrain dopamine neurons from lactacystin-induced neurodegeneration, but still prevented phosphorylated alpha-synuclein accumulation. In vivo experiment with control or GDNF-expressing viral vectors assessed alpha-synuclein pathology spread in the nigrostriatal pathway and lactacystin damage in the midbrain. GDNF overexpression reduced phosphorylated alpha-synuclein inclusions. Lactacystin-treated mice showed motor asymmetry and decreased spontaneous activity, exacerbated without AAV-GDNF pre-treatment. However, GDNF's neuroprotective effect could not be confirmed in vivo, due to side-effects from overexpression in the midbrain. Importantly, these findings show that GDNF continues to eliminate alpha-synuclein aggregation despite lactacystin-induced proteasome inhibition. Activating neurotrophic signaling pathways may protect against alpha-synuclein pathology in PD, even with impaired protein degradation mechanisms.

Keywords:  GDNF; Parkinson's disease; alpha-synuclein; gene overexpression; lactacystin; midbrain dopamine neurons; preformed fibrils; proteasome; viral vector

DOI:  https://doi.org/10.1016/j.ejps.2025.107048
Trends Biochem Sci. 2025 Feb 25. pii: S0968-0004(25)00028-3. [Epub ahead of print]

Balancing act: lipid-to-protein ratios steer the aggregation fate of α-synuclein.

Christian Blum, Mireille M A E Claessens.

  A recent report by Makasewicz et al. delineates how α-synuclein (αSyn) membrane-binding modes drive amyloid formation. Their in vitro data reveal a lipid-to-protein (L/P) ratio tipping point influencing fibril formation. Preliminary validation from existing literature supports that these findings are also relevant in cellular contexts, informing potential new disease-modulating strategies.

Keywords:  amyloid; lipid membranes; protein aggregation; protein–membrane interactions; vesicles; α-synuclein (αSyn)

DOI:  https://doi.org/10.1016/j.tibs.2025.02.001
Proteins. 2025 Feb 24.

Evaluation of the Ability of Wasp Venom Bioinspired Peptides (Fraternine-10 and Octovespin) in the Disaggregation and Anti-Aggregation of Amyloid-β Fibrils.

Yuri Alves de Oliveira Só, Caio Vinícius Sousa Costa, Luana Cristina Camargo, Letícia Germino Veras, Luiz Antônio Ribeiro Júnior, Márcia Renata Mortari, Ricardo Gargano.

  Many neurodegenerative diseases are directly related to the formation of toxic protein aggregates, such as Alzheimer's disease, which is associated with the aggregation of amyloid-beta (Aβ). In this context, protein fibrils are the hallmark of these neurodegenerative diseases. In this sense, developing compounds capable of preventing or reducing the formation of protein aggregation in the brain can be of fundamental importance for the curative treatment of these diseases. Animals' venom compounds are known to be selected for nervous system targets, therefore, they are considered an interesting platform for developing pharmacological tools. This work presents a study of the ligands Octovespin (bioinspired by the wasp venom Polybia occidentalis) and Fraternine-10 (bioinspired by the wasp venom Parachartergus fraternus) concerning the disaggregation and anti-aggregation of fibrils of Aβ(17-42) sheets. First, we performed in silico calculations using molecular docking and molecular dynamics simulations with 200 ns. The results indicate that Octovespin and Fraternine-10 interact with the Aβ protein fibrils throughout all simulation time. The RMSD, RMSF, number of hydrogen and radius of gyration values and the interactions with amino acids responsible for fibril aggregation demonstrate that both Octovespin and Fraternine-10 have a significant disaggregation potential, which corroborates the in vitro and in vivo experimental observations. Furthermore, experimental data of Fraternine-10 demonstrated an anti-aggregation effect, indicating that it can promote fibril disaggregation and prevent them from aggregating again to form oligomers. However, in vivo data of Fraternine-10 did not show improvement. Even though in vivo results were not promising, the in vitro and in silico discoveries qualify these molecules as potential sources for developing new candidates to become medicines against Alzheimer's disease.

Keywords:  Alzheimer's disease; anti‐aggregation effect; beta fibrils; disaggregation effect; docking molecular; dynamics molecular; wasp venom

DOI:  https://doi.org/10.1002/prot.26806
J Am Chem Soc. 2025 Feb 21.

Kinetic Steering of Amyloid Formation and Polymorphism by Canagliflozin, a Type-2 Diabetes Drug.

Alexander I P Taylor, Yong Xu, Martin Wilkinson, Pijush Chakraborty, Alice Brinkworth, Leon F Willis, Anastasia Zhuravleva, Neil A Ranson, Richard Foster, Sheena E Radford.

Amyloid formation is involved in widespread health conditions such as Alzheimer's disease, Parkinson's disease, and type-2 diabetes. Amyloid fibrils have a similar cross-β architecture, but fibrils formed by a single protein sequence can have diverse structures, varying with time, self-assembly conditions, and sequence modifications. Fibril structure has been proposed to be diagnostic of disease, but why different structures result under different conditions, especially in vitro, remains elusive. We previously identified a small molecule, YX-I-1, which inhibits in vitro amyloid formation by islet amyloid polypeptide (IAPP), a peptide hormone whose amyloid formation is involved in type-2 diabetes. Here, using YX-I-1 as a lead, we identified regulator-approved drugs with similar structures by chemical similarity analysis and substructure searches and monitored the effect of 24 of these potential ligands on IAPP amyloid assembly in vitro. We show that one such compound, canagliflozin (Invokana), a type-2 diabetes drug already in clinical use, can strongly delay the kinetics of IAPP amyloid formation, an activity independent of its intended mode of action [sodium-glucose linked transporter 2 (SGLT2) inhibitor] that may have important therapeutic implications. Combining analysis of amyloid self-assembly kinetics, biophysical characterization of monomer and fibril binding, and cryo-EM of the assembly products, we show that YX-I-1 and canagliflozin target IAPP early in aggregation, remodeling the energy landscape of primary nucleation and profoundly altering the resulting fibril structures. Early binding events thus imprint long-lasting effects on the amyloid structures that form.

DOI: https://doi.org/10.1021/jacs.4c16743
Exp Physiol. 2025 Feb 21.

Intact microdissection of stellate ganglia in a Parkinson's disease model reveals aggregation of mutant human α-synuclein in their cell bodies.

Bonn Lee, Shiraz Ahmad, Charlotte E Edling, Fiona E N LeBeau, Kamalan Jeevaratnam.

  Cardiac dysautonomia plays an important role in understanding Parkinson's disease (PD), with recent studies highlighting the presence of α-synuclein in cardiac tissue. We hypothesise that sympathetic dysregulation observed in PD may involve pathological changes caused by α-synuclein in stellate ganglia (SG). This study aimed to investigate α-synucleinopathy in SG of the genetic PD murine animal model. Mice overexpressing Ala30Pro (A30P) mutant α-synuclein were used. We here demonstrate a technique for meticulously dissecting SG. The collected SG from the transgenic mice were immunolabelled with neuronal markers, A30P human mutant α-synuclein and anti-α-synuclein aggregates. A30P mutant α-synuclein protein was expressed in the sympathetic neuronal (tyrosine hydroxylase (TH)-positive) cell bodies. Approximately 27% of the TH-positive cell bodies expressed the A30P mutant α-synuclein protein. The mutant protein was densely localised at the cardiopulmonary pole of the SG. Additionally, we observed that the A30P mutant protein formed fibril aggregation in the SG. Our findings suggest that α-synucleinopathy in the PD animal model can affect the sympathetic autonomic nervous system, providing insight for further research into targeting α-synuclein pathology in the SG as a potential link between cardiac dysautonomia and PD.

Keywords:  Parkinson's disease; SUDPAR; cardiac dysautonomia; stellate ganglia; α‐synuclein

DOI:  https://doi.org/10.1113/EP092261
Int J Mol Sci. 2025 Feb 14. pii: 1615. [Epub ahead of print]26(4):

α-Synuclein Degradation in Brain Pericytes Is Mediated via Akt, ERK, and p38 MAPK Signaling Pathways.

Miki Yokoya, Fuyuko Takata, Takuro Iwao, Junichi Matsumoto, Yasuyoshi Tanaka, Hisataka Aridome, Miho Yasunaga, Junko Mizoguchi, Kazunori Sano, Shinya Dohgu.

  Parkinson's disease (PD) is characterized by widespread distribution of Lewy bodies, which are composed of phosphorylated and aggregated forms of α-Synuclein (α-Syn), in the brain. Although the accumulation and propagation of α-Syn contribute to the development of PD, the involvement of the blood-brain barrier (BBB) in these processes remains unknown. Pericytes, one of the cell types that constitute the BBB, degrade various forms of α-Syn. However, the detailed mechanisms involved in α-Syn degradation by pericytes remain poorly understood. Therefore, in this study, we aimed to determine the ability of the BBB-constituting cells, particularly primary cultures of rat pericytes, brain endothelial cells, and astrocytes, to degrade α-Syn. After α-Syn uptake by the cells, intracellular α-Syn decreased only in pericytes. This pericyte-specific α-Syn decrease was inhibited by an autophagy inhibitor, bafilomycin A1, and a proteasome inhibitor, MG132. siRNA-mediated knockdown of degradation enzymes or familial PD-associated genes, including cathepsin D, DJ-1, and LRRK2, did not affect α-Syn clearance in pericytes. However, pharmacological inhibitors of Akt, ERK, and p38 MAPK inhibited α-Syn degradation by pericytes. In conclusion, our results suggest that α-Syn degradation by pericytes is mediated by an autophagy-lysosome system and a ubiquitin-proteasome system via α-Syn-activated Akt, ERK, and p38 MAPK signaling pathways.

Keywords:  Akt; ERK; Parkinson’s disease; alpha-Synuclein; autophagy; blood–brain barrier; p38 MAPK; pericyte; ubiquitin–proteasome system

DOI:  https://doi.org/10.3390/ijms26041615
J Am Chem Soc. 2025 Feb 25.

Transition-State-Dependent Spontaneous Generation of Reactive Oxygen Species by Aβ Assemblies Encodes a Self-Regulated Positive Feedback Loop for Aggregate Formation.

Michael W Chen, Xiaokang Ren, Xiaowei Song, Naixin Qian, Yuefeng Ma, Wen Yu, Leshan Yang, Wei Min, Richard N Zare, Yifan Dai.

Amyloid-β (Aβ) peptides exhibit distinct biological activities across multiple physical length scales, including monomers, oligomers, and fibrils. The transition from Aβ monomers to pathological aggregates correlates with the emergence of chemical toxicity, which plays a critical role in the progression of neurodegenerative disorders. However, the relationship between the physical state of Aβ assemblies and their chemical toxicity remains poorly understood. Here, we show that Aβ assemblies can spontaneously generate reactive oxygen species (ROS) through transition-state-specific inherent nonenzymatic redox activity. During the transition from initial monomers to intermediate oligomers or condensates to final fibrils, interfacial electrochemical environments emerge and vary at the liquid-liquid and liquid-solid interfaces. Determined by the vibrational Stark effect using electronic pre-resonance stimulated Raman scattering microscopy, the interfacial field of such assemblies is on the order of 10 MV/cm. Interfacial activity, which depends on the Aβ transition state, can modulate the spontaneous oxidation of hydroxide anions, which leads to the formation of hydroxyl radicals. Interestingly, this redox activity modifies the chemical composition of Aβ and establishes a self-regulated positive feedback loop that accelerates aggregation and promotes fibril formation, which represents a new functioning mechanism of Aβ aggregation beyond physical cross-linking. Leveraging this mechanistic insight, we identified small molecules capable of disrupting the feedback loop by scavenging hydroxyl radicals or perturbing the interface, thereby inhibiting fibril formation. Our findings provide a nonenzymatic model of neurotoxicity and reveal the critical role of physical interfaces in modulating the chemical dynamics of biomolecular assemblies. These results offer a novel framework for therapeutic intervention in Alzheimer's disease and related neurodegenerative disorders.

DOI: https://doi.org/10.1021/jacs.4c15532
Neurotherapeutics. 2025 Feb 25. pii: S1878-7479(25)00035-2. [Epub ahead of print] e00557

The therapeutic potential of (R)-carvedilol in Huntington's disease through enhancement of autophagy-lysosomal pathway via GSK-3β inhibition.

Chih-Yuan Cheng, Kai-Po Chen, Tien-Sheng Tseng, Kuo-Feng Hua, Tz-Chuen Ju.

  Huntington's disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the huntingtin (Htt) gene, leading to the aggregation of mutant huntingtin protein (mHTT) in cells, particularly in cortical and striatal neurons. This results in involuntary movements, cognitive impairment, and emotional instability. One of the critical pathogenic mechanisms in HD is impaired autophagy, which plays a vital role in cellular homeostasis by degrading damaged organelles and misfolded proteins through the formation of autophagosomes that fuse with lysosomes. However, the aggregation of mHTT disrupts autophagic function, leading to the accumulation of mHTT and exacerbating the disease's pathogenesis. Carvedilol is an established clinical medication used to treat hypertension and congestive heart failure. It exerts protective effects by blocking both β1-and β2-adrenergic receptors, reducing sympathetic nervous activity, and promoting vasodilation through α1-adrenergic blockade. Carvedilol has been shown to possess antioxidant and anti-inflammatory properties. In this study, we demonstrate that (R)-carvedilol promotes the nuclear translocation of the transcription factor binding to IGHM enhancer 3 (TFE3) by reducing glycogen synthase-3β (GSK-3β) activation, which increases the expression of autophagy-related proteins and facilitates the autophagy-lysosomal pathway (ALP), thereby enhancing mHTT degradation. Additionally, systemic administration of (R)-carvedilol improves mHTT degradation, provides neuroprotection, and inhibits gliosis, effectively ameliorating behavioral impairments and improving disease progression. Overall, these findings indicate that (R)-carvedilol has therapeutic potential for managing HD by promoting autophagy, facilitating the clearance of mHTT aggregates, and demonstrating advantageous properties in an HD transgenic mouse model, highlighting its promise as a treatment option for neurodegenerative diseases.

Keywords:  Autophagy-lysosomal pathway (ALP); Cathepsin B (CTSB); Glycogen synthase 3β (GSK-3β); Mutant huntingtin (mHTT); Transcription factor binding to IGHM enhancer 3 (TFE3)

DOI:  https://doi.org/10.1016/j.neurot.2025.e00557
Free Radic Biol Med. 2025 Feb 25. pii: S0891-5849(25)00012-7. [Epub ahead of print]230 283-293

Edaravone mitigates TDP-43 mislocalization in human amyotrophic lateral sclerosis neurons with potential implication of the SIRT1-XBP1 pathway.

Satsuki Mikuriya, Tomo Takegawa-Araki, Makoto Tamura.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss along with pathological mislocalization of TAR DNA-binding protein 43 (TDP-43), a protein implicated in RNA metabolism. Although edaravone, a free-radical scavenger, has been approved for ALS treatment, its precise mechanism of action is not fully understood, particularly in relation to TDP-43 pathology. Here, we investigated the effects of edaravone on induced pluripotent stem cell (iPSC)-derived motor neurons in a patient with ALS harboring a TDP-43 mutation. Our results demonstrated that edaravone significantly attenuated neurodegeneration, as evidenced by neurite preservation, neuronal cell death reduction, and correction of aberrant cytoplasmic localization of TDP-43. These neuroprotective effects were not observed with vitamin C, indicating a unique mechanism of action for edaravone, distinct from its antioxidative properties. RNA sequencing revealed that edaravone rapidly modulated gene expression, including protein quality control pathway, such as the ubiquitin-proteasome system. Further analysis identified X-box binding protein (XBP1), a key regulator of the endoplasmic reticulum stress response, as a critical factor in the therapeutic effects of edaravone. This study suggests that edaravone may offer a multifaceted therapeutic approach for ALS by targeting oxidative stress and TDP-43 mislocalization through distinct molecular pathways.

Keywords:  Amyotrophic lateral sclerosis; Antioxidants; Edaravone; TDP-43

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.01.012
Biomolecules. 2025 Feb 02. pii: 214. [Epub ahead of print]15(2):

α-Synuclein Iron-Responsive-Element RNA and Iron Regulatory Protein Affinity Is Specifically Reduced by Iron in Parkinson's Disease.

Mateen A Khan.

  α-Synuclein (α-Syn) is implicated in the pathophysiology of Parkinson's disease (PD) and plays a significant role in neuronal degeneration. Iron response proteins (IRPs) bind to iron response elements (IREs) found in the 5'-untranslated regions (5'-UTRs) of the messenger RNA that encode the α-Syn gene. This study used multi-spectroscopic approach techniques to investigate the impact of iron on α-Syn IRE RNA binding to IRP1. The formation of a stable complex between α-Syn RNA and IRP1 was suggested by fluorescence quenching results. Fluorescence measurements showed that α-Syn RNA and IRP1 had a strong interaction, with a binding constant (Ka) of 21.0 × 106 M-1 and 1:1 binding stoichiometry. About one binding site per IRP1 molecule was suggested by the α-Syn RNA binding. The Ka for α-Syn RNA•IRP1 with added Fe2+ (50 μM) was 6.4 μM-1. When Fe2+ was added, the Ka of α-Syn RNA•IRP1 was reduced by 3.3 times. These acquired Ka values were used to further understand the thermodynamic characteristics of α-Syn RNA•IRP1 interactions. The thermodynamic properties clearly suggested that α-Syn RNA binding to IRP1 was an entropy-favored and enthalpy-driven event, with significant negative ΔH and small positive ΔS. For α-Syn RNA•IRP1, the Gibbs free energy (ΔG) was -43.7 ± 2.7 kJ/mol, but in the presence of Fe2+, it was -36.3 ± 2.1 kJ/mol. These thermodynamic calculations indicated that hydrogen bonding as well as van der Waals interactions might help to stabilize the complex formation. Additionally, far-UV CD spectra verified α-Syn RNA•IRP1 complex formation, and α-Syn RNA and Fe2+ induce secondary structural alteration of IRP1. According to our findings, iron alters the hydrogen bonding in α-Syn RNA•IRP1 complexes and induces a structural change in IRP1. This suggests that iron selectively affects the thermodynamics of these RNA-protein interactions.

Keywords:  IRP1; Parkinson’s disease; RNA–protein binding; circular dichroism; fluorescence; neurodegenerative diseases; thermodynamics; α-synuclein IRE RNA

DOI:  https://doi.org/10.3390/biom15020214