bims-proned 2025-06-01 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–06–01
sixteen papers selected by
Verena Kohler, Umeå University

Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses.
Nanoplatforms Targeting Intrinsically Disordered Protein Aggregation for Translational Neuroscience Applications.
On the Potential Role of Phytate Against Neurodegeneration: It Protects Against Fe3+-Catalyzed Degradation of Dopamine and Ascorbate and Against Fe3+-Induced Protein Aggregation.
An adenine model of inborn metabolism errors alters TDP-43 aggregation and reduces its toxicity in yeast revealing insights into protein misfolding diseases.
Tau from SPAM Transgenic Mice Exhibit Potent Strain-Specific Prion-Like Seeding Properties Characteristic of Human Neurodegenerative Diseases.
Intracellular Inclusions Induced by Patient-Derived and Amplified α-Synuclein Aggregates Are Morphologically Indistinguishable.
β-synuclein blocks α-synuclein condensate fusion to disrupt the maturation of phase separation.
Inhibition of α-synuclein aggregation by MCC950 attenuates dopaminergic neuronal damage in MN9D cells.
UPS10 inhibits the degradation of α-synuclein, a pathogenic factor associated with Parkinson's disease, by inhibiting chaperone-mediated autophagy.
Complement C4 exacerbates astrocyte-mediated neuroinflammation and promotes α-synuclein pathology in Parkinson's disease.
Exploring Protein Misfolding in Amyotrophic Lateral Sclerosis: Structural and Functional Insights.
Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates.
Chronic stress induces depression-like behaviors and Parkinsonism via upregulating α-synuclein.
Overexpression in Plasmodium falciparum of an intrinsically disordered protein segment of PfUT impairs the parasite's proteostasis and reduces its growth rate.
Mechanisms of Alpha-Synuclein-Seeded Aggregation in Neurons Revealed by Fluorescence Lifetime Imaging.
Molecular Insight into Amyloid Fibril-Templated Aggregation of Biomarkers.

Cells. 2025 05 08. pii: 680. [Epub ahead of print]14(10):

Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses.

Enza Maria Verde, Valentina Secco, Andrea Ghezzi, Jessica Mandrioli, Serena Carra.

  Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurodegenerative disorders that share common genes and pathomechanisms and are referred to as the ALS-FTD spectrum. A hallmark of ALS-FTD pathology is the abnormal aggregation of proteins, including Cu/Zn superoxide dismutase (SOD1), transactive response DNA-binding protein 43 (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS/TLS), and dipeptide repeat proteins resulting from C9orf72 hexanucleotide expansions. Genetic mutations linked to ALS-FTD disrupt protein stability, phase separation, and interaction networks, promoting misfolding and insolubility. This review explores the molecular mechanisms underlying protein aggregation in ALS-FTD, with a particular focus on TDP-43, as it represents the main aggregated species inside pathological inclusions and can also aggregate in its wild-type form. Moreover, this review describes the protective mechanisms activated by the cells to prevent protein aggregation, including molecular chaperones and post-translational modifications (PTMs). Understanding these regulatory pathways could offer new insights into targeted interventions aimed at mitigating cell toxicity and restoring cellular function.

Keywords:  ALS-FTD; TDP-43; post-translational modifications; protein aggregation; stress granules

DOI:  https://doi.org/10.3390/cells14100680
Nanomaterials (Basel). 2025 May 08. pii: 704. [Epub ahead of print]15(10):

Nanoplatforms Targeting Intrinsically Disordered Protein Aggregation for Translational Neuroscience Applications.

Chih Hung Lo, Lenny Yi Tong Cheong, Jialiu Zeng.

  Intrinsically disordered proteins (IDPs), such as tau, beta-amyloid (Aβ), and alpha-synuclein (αSyn), are prone to misfolding, resulting in pathological aggregation and propagation that drive neurodegenerative diseases, including Alzheimer's disease (AD), frontotemporal dementia (FTD), and Parkinson's disease (PD). Misfolded IDPs are prone to aggregate into oligomers and fibrils, exacerbating disease progression by disrupting cellular functions in the central nervous system, triggering neuroinflammation and neurodegeneration. Furthermore, aggregated IDPs exhibit prion-like behavior, acting as seeds that are released into the extracellular space, taken up by neighboring cells, and have a propagating pathology across different regions of the brain. Conventional inhibitors, such as small molecules, peptides, and antibodies, face challenges in stability and blood-brain barrier penetration, limiting their efficacy. In recent years, nanotechnology-based strategies, such as multifunctional nanoplatforms or nanoparticles, have emerged as promising tools to address these challenges. These nanoplatforms leverage tailored designs to prevent or remodel the aggregation of IDPs and reduce associated neurotoxicity. This review discusses recent advances in nanoplatforms designed to target tau, Aβ, and αSyn aggregation, with a focus on their roles in reducing neuroinflammation and neurodegeneration. We examine critical aspects of nanoplatform design, including the choice of material backbone and targeting moieties, which influence interactions with IDPs. We also highlight key mechanisms including the interaction between nanoplatforms and IDPs to inhibit their aggregation, redirect aggregation cascade towards nontoxic, off-pathway species, and disrupt fibrillar structures into soluble forms. We further outline future directions for enhancing IDP clearance, achieving spatiotemporal control, and improving cell-specific targeting. These nanomedicine strategies offer compelling paths forward for developing more effective and targeted therapies for neurodegenerative diseases.

Keywords:  aggregation; fibrillization; intrinsically disordered protein; nanomedicine; nanoplatform; neurodegeneration; neuroinflammation; oligomerization

DOI:  https://doi.org/10.3390/nano15100704
Int J Mol Sci. 2025 May 16. pii: 4799. [Epub ahead of print]26(10):

On the Potential Role of Phytate Against Neurodegeneration: It Protects Against Fe3+-Catalyzed Degradation of Dopamine and Ascorbate and Against Fe3+-Induced Protein Aggregation.

Samantha Rebeca Godoy, Pilar Sanchis, Juan Frau, Bartolomé Vilanova, Miquel Adrover.

  Myo-inositol-1,2,3,4,5,6-hexakisphosphate (IP6) is commonly found in plant-derived foods and has important pharmacological properties against many pathologies. One of them appears to be neurodegeneration, which is notably stimulated by dysregulated metal metabolism. Consequently, we explore the role of IP6 in mitigating neurodegenerative events catalyzed by dysregulated free iron. More precisely, we performed spectrophotometric measurements in aqueous solutions to investigate the ability of IP6 to chelate Fe3+ and inhibit its role in catalyzing the oxidative degradation of dopamine and ascorbic acid, two key molecules in neuronal redox systems. Our results demonstrate that IP6 effectively prevents the formation of harmful intermediates, such as neuromelanin and reactive oxygen species, which are linked to neuronal damage. Additionally, we assessed the effect of IP6 on Fe3+-induced protein aggregation, focusing on α-synuclein, which is closely associated with Parkinson's disease. Our data reveal that IP6 accelerates the conversion of toxic α-synuclein oligomers into less harmful amyloid fibrils, thereby reducing their neurotoxic potential. Our findings highlight the dual function of IP6 as a potent Fe3+ chelator and modulator of protein aggregation pathways, reinforcing its potential as a neuroprotective agent. Consequently, IP6 offers promising therapeutic potential for mitigating the progression of neurodegenerative disorders such as Parkinson's and Alzheimer's diseases.

Keywords:  ascorbic acid; dopamine; phytic acid; α-synuclein

DOI:  https://doi.org/10.3390/ijms26104799
Microb Cell. 2025 ;12 119-130

An adenine model of inborn metabolism errors alters TDP-43 aggregation and reduces its toxicity in yeast revealing insights into protein misfolding diseases.

Sangeun Park, Sei-Kyoung Park, Peter Blair, Susan W Liebman.

  TDP-43 is linked to human diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Expression of TDP-43 in yeast is known to be toxic, cause cells to elongate, form liquid-like aggregates, and inhibit autophagy and TOROID formation. Here, we used the apt1∆ aah1∆ yeast model of inborn errors of metabolism, previously shown to lead to intracellular adenine accumulation and adenine amyloid-like fiber formation, to explore interactions with TDP-43. Results show that the double deletion shifts the TDP-43 aggregates from liquid-like droplets toward a more amyloid-like state. At the same time the deletions reduce TDP-43's effects on toxicity, cell morphology, autophagy, and TOROID formation without affecting the level of TDP-43. This suggests that the liquid-like droplets rather than amyloid-like TDP-43 aggregates are responsible for the deleterious effects in yeast. How the apt1∆ aah1∆ deletions alter TDP-43 aggregate formation is not clear. Possibly, it results from adenine and TDP-43 fiber interactions as seen for other heterologous fibers. This work offers new insights into the potential interactions between metabolite-based amyloids and pathological protein aggregates, with broad implications for understanding protein misfolding diseases.

Keywords:  ALS; FRAP; TDP-43; liquid-like droplets; metabolism disorders; metabolite-based amyloids; yeast

DOI:  https://doi.org/10.15698/mic2025.05.850
Neuromolecular Med. 2025 May 30. 27(1): 44

Tau from SPAM Transgenic Mice Exhibit Potent Strain-Specific Prion-Like Seeding Properties Characteristic of Human Neurodegenerative Diseases.

Ethan D Smith, Giavanna Paterno, Brach M Bell, Kimberly-Marie M Gorion, Stefan Prokop, Benoit I Giasson.

  Tauopathies, including Alzheimer's disease and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), are characterized by the aberrant aggregation of tau protein into neurofibrillary tangles. Despite extensive studies on tau aggregation, the mechanisms of tau misfolding and propagation remain incompletely understood. In this study, we utilize the SPAM (S320F/P301S) tau transgenic mouse model, which expresses 0N4R human tau with two FTDP-17 mutations, to investigate the biochemical properties and seeding potential of misfolded tau from these mice. Sarkosyl extraction and ultracentrifugation were employed to isolate detergent-insoluble tau aggregates (SPAM-tau) from aged SPAM mice. These aggregates were then tested for their prion-type seeding activity in an established HEK293T cell model comparing the induced aggregation of wild-type and mutant forms of human and murine tau. Our results show that SPAM-tau exhibits distinct and vigorous prion-like seeding properties, inducing the aggregation of human and murine tau homologues with the formation of amyloidogenic (Thioflavin S-positive) inclusions. Importantly, SPAM-tau aggregates can facilitate the prion-type misfolding of wild-type and mutant forms of human and mouse tau. We demonstrated that these induced tau aggregates are able to be further transmitted in passaging studies. Furthermore, SPAM-tau preferentially templated 4R tau isoforms, sharing strain-like seeding properties with insoluble tau derived from the brains of individuals with progressive supranuclear palsy (PSP-tau). In summary, these findings enhance our understanding of tau aggregation and propagation, suggesting that SPAM-tau may serve as a valuable tool for studying tauopathies and evaluating potential therapeutic strategies aimed at halting tau misfolding and propagation.

Keywords:  Alzheimer’s disease; FTDP-17; Prion; Progressive supranuclear palsy; Seeding; Tau; Transgenic mice

DOI:  https://doi.org/10.1007/s12017-025-08850-4
Cells. 2025 05 09. pii: 684. [Epub ahead of print]14(10):

Intracellular Inclusions Induced by Patient-Derived and Amplified α-Synuclein Aggregates Are Morphologically Indistinguishable.

Rabab Al-Lahham, Mark E Corkins, Mohd Ishtikhar, Prakruti Rabadia, Santiago Ramirez, Victor Banerjee, Mohammad Shahnawaz.

  Lewy Body Disease (LBD) and Multiple System Atrophy (MSA) are synucleinopathies with distinct prognoses and neuropathologies, however, with overlapping clinical symptoms. Different disease characteristics are proposed to be determined by distinct conformations of alpha-synuclein (α-Syn) aggregates, which can self-propagate and spread between cells via a prion-like mechanism. The goal of this study is to investigate whether α-syn aggregates amplified from brain and CSF samples of LBD and MSA patients using the Seed Amplification Assay (SAA) maintain α-Syn seeding properties similar to those of α-syn aggregates derived from patients' brains. To address this, SAA-amplified and un-amplified α-Syn aggregates from LBD and MSA patients' brains, as well as SAA-amplified α-Syn aggregates from LBD and MSA patients' CSF samples, were used to treat synuclein biosensor cells, and induced intracellular α-Syn inclusions were analyzed by confocal microscopy. Our data indicate that induced α-Syn aggregates from LBD and MSA patients' brains have similar seeding properties and morphological characteristics in the α-Syn biosensor cells as those amplified from LBD and MSA patients' brains, as well as those amplified from LBD and MSA patients' CSF samples. In this study, we demonstrated that, regardless of the source of aggregates, the seeds from LBD and MSA produce cellular accumulation of α-Syn with distinct morphologies, confirming the presence of different conformational strains of α-Syn in LBD and MSA and allowing us to differentiate synucleinopathies based on the morphology of aggregates and seeding properties.

Keywords:  Parkinson’s disease; SAA; aggregation; biosensor cells; multiple system atrophy; α-synuclein

DOI:  https://doi.org/10.3390/cells14100684
Cell Rep. 2025 May 28. pii: S2211-1247(25)00532-7. [Epub ahead of print]44(6): 115761

β-synuclein blocks α-synuclein condensate fusion to disrupt the maturation of phase separation.

Bingkuan Xu, Wenyuan He, Fengshuo Fan, Shuhan Chen, Min Zhu, Yanjun Hou, Lingjun Zheng, Haijia Yu, Yinghui Liu.

  The abnormal accumulation of α-synuclein (α-Syn) is a key feature of Parkinson's disease (PD) and other synucleinopathies. α-Syn undergoes liquid-liquid phase separation (LLPS) to accelerate the amyloid aggregation. β-synuclein (β-Syn) colocalizes with α-Syn and affects its aggregation. It remains poorly understood how the LLPS of α-Syn is regulated by β-Syn. Here, we find that β-Syn co-condenses with α-Syn, negatively regulating the LLPS of α-Syn. The mobility of α-Syn is reduced in α-Syn/β-Syn coacervates, diminishing the condensate fusion. β-Syn blocks the condensate growth and maturation of α-Syn phase separation but cannot reverse the condensation pathway. We show that dementia with Lewy bodies (DLB)-associated β-Syn mutations impair β-Syn's inhibitory role in α-Syn condensate fusion. β-Syn, but not its disease-associated mutants, can ameliorate α-Syn-caused dopaminergic neuron degeneration in Caenorhabditis elegans. These findings provide insights into the neuroprotection of β-Syn and the targeting of α-Syn phase separation in disease treatment.

Keywords:  CP: Neuroscience; LLPS; PD; Parkinson’s disease; amyloid aggregation; condensate fusion; liquid-liquid phase separation; α-synuclein; β-synuclein

DOI:  https://doi.org/10.1016/j.celrep.2025.115761
Eur J Pharmacol. 2025 May 26. pii: S0014-2999(25)00528-X. [Epub ahead of print] 177774

Inhibition of α-synuclein aggregation by MCC950 attenuates dopaminergic neuronal damage in MN9D cells.

Huiwen Gao, Yingneng Liang, Mengfei Wang, Wen Li, Wei Zheng, Zitong Wang, Guangqiang Sun, Hongchun Liu, Ming Liu, Yu Zhang.

  Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons and the pathological aggregation of α-synuclein, which drives neurodegeneration. The NLRP3 inflammasome inhibitor MCC950 has shown neuroprotective effects in various PD models, but its direct impact on α-synuclein aggregation remains unclear. Here, we investigated the effects of MCC950 in an α-synuclein-overexpressing MN9D dopaminergic neuronal model. MCC950 significantly alleviated α-synuclein-induced neuronal damage, as evidenced by improved cell viability, reduced apoptosis, and downregulated tumor necrosis factor-alpha (TNF-α) expression. Proteomic analysis revealed that MCC950 modulates protein processing in the endoplasmic reticulum (ER), potentially alleviating stress-induced protein misfolding. Molecular docking and biochemical assays demonstrated that MCC950 directly binds to the C-terminal region of α-synuclein, inhibiting its aggregation. Additionally, MCC950 upregulated heat shock protein 70 (HSP70), a molecular chaperone that suppresses α-synuclein oligomerization. Notably, the neuroprotective effects of MCC950 were independent of autophagy modulation or NLRP3 inflammasome inhibition in this model. These findings highlight MCC950 as a multi-target therapeutic agent that directly inhibits α-synuclein aggregation, offering a promising strategy for treating PD and related α-synucleinopathies.

Keywords:  MCC950; Parkinson’s disease; neuroprotection; α-synuclein

DOI:  https://doi.org/10.1016/j.ejphar.2025.177774
J Biol Chem. 2025 May 24. pii: S0021-9258(25)02142-8. [Epub ahead of print] 110292

UPS10 inhibits the degradation of α-synuclein, a pathogenic factor associated with Parkinson's disease, by inhibiting chaperone-mediated autophagy.

Sergei Anisimov, Masahiko Takahashi, Taichi Kakihana, Yoshinori Katsuragi, Junya Sango, Takayuki Abe, Masahiro Fujii.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons, particularly in the substantia nigra of the brain. α-Synuclein is a major causative factor in both familial and sporadic forms of PD, and its protein aggregates play critical roles in neuronal cell death and PD pathogenesis. This study explored the role of ubiquitin-specific protease 10 (USP10) in the regulation of α-synuclein in neuronal cells. Knockdown of USP10 (USP10-KD) in SH-SY5Y neuronal cells led to a reduction in α-synuclein levels, which was reversed by inhibiting chaperone-mediated autophagy (CMA) through LAMP2A depletion, a protein essential for CMA. A novel CMA reporter with a specific CMA degradation motif further demonstrated that USP10-KD activated CMA in neuronal cells. In addition, USP10 overexpression increased the levels of both wild-type and five PD-associated α-synuclein mutants, whereas a deubiquitinase-deficient USP10 mutant did not increase α-synuclein levels. This study provides new insights into the mechanisms that regulate α-synuclein proteostasis and highlights USP10 as a promising drug target for PD.

Keywords:  Parkinson’s disease; USP10; α-synuclein; сhaperone-mediated autophagy

DOI:  https://doi.org/10.1016/j.jbc.2025.110292
NPJ Parkinsons Dis. 2025 May 28. 11(1): 141

Complement C4 exacerbates astrocyte-mediated neuroinflammation and promotes α-synuclein pathology in Parkinson's disease.

Wenkai Zou, Liang Kou, Yiming Wang, Zongjie Jin, Nian Xiong, Tao Wang, Yun Xia.

Complement C4, implicated in neuroinflammation and synaptic dysfunction, plays a poorly defined role in Parkinson's disease (PD). Here, we demonstrate elevated C4 levels in PD patient plasma and the substantia nigra of α-synuclein preformed fibril (α-syn PFF)-injected mice, correlating with disease severity. α-syn PFF treatment induces complement C4 expression, particularly in neurons, with astrocytes further enhancing this response. Complement C4 was found to amplify astrocytic inflammatory responses, leading to increased neuronal apoptosis and synaptic damage. Additionally, conditioned media from astrocytes treated with α-syn PFF and complement C4 accelerated α-syn aggregation and synaptic loss in cultured neurons. In vivo, complement C4 exacerbated motor dysfunction, dopaminergic neuronal loss, and α-syn pathology in α-syn PFF-injected mice. These findings reveal that complement C4 significantly contributes to the neuroinflammatory environment and α-syn pathology in PD, highlighting its potential as a therapeutic target for mitigating neurodegeneration in this disorder.

DOI: https://doi.org/10.1038/s41531-025-01005-z
Biomedicines. 2025 May 09. pii: 1146. [Epub ahead of print]13(5):

Exploring Protein Misfolding in Amyotrophic Lateral Sclerosis: Structural and Functional Insights.

Ouliana Ivantsik, Themis P Exarchos, Aristidis G Vrahatis, Panagiotis Vlamos, Marios G Krokidis.

  Protein functionality depends on its proper folding, making protein misfolding crucial for the function of proteins and, by extension, cells and the whole organism. Increasing evidence supports the role of protein misfolding in the pathogenesis of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). ALS is a rapidly progressive disease diagnosed at a prevalence of 5 cases per 100,000, with approximately 2-3 patients per 100,000 diagnosed each year. To date, there is no cure, and the disease usually leads to death within 2 to 5 years from diagnosis. There are two types of the disorder: familial ALS (fALS), accounting for approximately 10% of cases, and sporadic (sALS), accounting for the remaining 90%. The hallmark of ALS, regardless of type, is the protein aggregates found in patients' tissues. This suggests that the disruption of proteostasis plays a critical role in the development of the disease. Herein, we stress the distinct factors that lead to protein misfolding and aggregate formation in ALS. Specifically, we highlight several triggering factors affecting protein misfolding, namely mutations, errors in the processes of protein production and trafficking, and failures of folding and chaperone machinery. Gaining a deeper understanding of protein aggregation will improve our comprehension of disease pathogenesis and potentially uncover new therapeutic approaches.

Keywords:  aggregation; amyotrophic lateral sclerosis; mutations; prion; protein misfolding; superoxide dismutase 1

DOI:  https://doi.org/10.3390/biomedicines13051146
Cell. 2025 May 15. pii: S0092-8674(25)00509-4. [Epub ahead of print]

Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates.

Xiao Yan, David Kuster, Priyesh Mohanty, Jik Nijssen, Karina Pombo-García, Jorge Garcia Morato, Azamat Rizuan, Titus M Franzmann, Aleksandra Sergeeva, Anh M Ly, Feilin Liu, Patricia M Passos, Leah George, Szu-Huan Wang, Jayakrishna Shenoy, Helen L Danielson, Busra Ozguney, Alf Honigmann, Yuna M Ayala, Nicolas L Fawzi, Dennis W Dickson, Wilfried Rossoll, Jeetain Mittal, Simon Alberti, Anthony A Hyman.

  Cytosolic aggregation of the nuclear protein TAR DNA-binding protein 43 (TDP-43) is associated with many neurodegenerative diseases, but the triggers for TDP-43 aggregation are still debated. Here, we demonstrate that TDP-43 aggregation requires a double event. One is up-concentration in stress granules beyond a threshold, and the other is oxidative stress. These two events collectively induce intra-condensate demixing, giving rise to a dynamic TDP-43-enriched phase within stress granules, which subsequently transition into pathological aggregates. Intra-condensate demixing of TDP-43 is observed in iPS-motor neurons, a disease mouse model, and patient samples. Mechanistically, intra-condensate demixing is triggered by local unfolding of the RRM1 domain for intermolecular disulfide bond formation and by increased hydrophobic patch interactions in the C-terminal domain. By engineering TDP-43 variants resistant to intra-condensate demixing, we successfully eliminate pathological TDP-43 aggregates in cells. We suggest that up-concentration inside condensates followed by intra-condensate demixing could be a general pathway for protein aggregation.

Keywords:  ALS; FTD; TDP-43; biomolecular condensate; intra-condensate demixing; neurodegenerative diseases; oxidative stress; phase separation; protein aggregation; stress granules

DOI:  https://doi.org/10.1016/j.cell.2025.04.039
NPJ Parkinsons Dis. 2025 May 28. 11(1): 139

Chronic stress induces depression-like behaviors and Parkinsonism via upregulating α-synuclein.

Danhao Xia, Min Xiong, Yingxu Yang, Xin Wang, Qiang Chen, Sheng Li, Lanxia Meng, Zhentao Zhang.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the aggregation of α-synuclein (α-syn) and the nigrostriatal dopaminergic neuronal degeneration. Depression is one of the most common non-motor symptoms of PD patients. However, the pathogenic connection between PD and depression is not well understood. Herein, we report that chronic stress upregulates the expression of α-syn in the mouse brain. Overexpression of α-syn in the hippocampus replicates depressive-like phenotypes, whereas the genetic deletion of α-syn enhances resistance to chronic stress. Furthermore, chronic stress in early life promoted the deposition of α-syn aggregates in a transgenic mouse model that overexpresses human A53T mutant α-syn (A53T mice). Chronic stress also exacerbated dopaminergic degeneration and motor impairments in A53T mice. Strikingly, α-syn inclusions were also observed in the brains of some aged non-transgenic mice subjected to chronic stress. Together, our findings suggest that chronic stress upregulates α-synuclein expression, resulting in depression-like behaviors and parkinsonism.

DOI: https://doi.org/10.1038/s41531-025-00998-x
Front Cell Infect Microbiol. 2025 ;15 1565814

Overexpression in Plasmodium falciparum of an intrinsically disordered protein segment of PfUT impairs the parasite's proteostasis and reduces its growth rate.

Yunuen Avalos-Padilla, Inés Bouzón-Arnáiz, Miriam Ramírez, Claudia Camarero-Hoyos, Marc Orozco-Quer, Elsa M Arce, Diego Muñoz-Torrero, Xavier Fernàndez-Busquets.

  The proteome of Plasmodium falciparum exhibits a marked propensity for aggregation. This characteristic results from the parasite's AT-rich genome, which encodes numerous proteins with long asparagine-rich stretches and low structural complexity, which lead to abundant intrinsically disordered regions. While this poses challenges for the parasite, the propensity for protein aggregation may also serve functional roles, such as stress adaptation, and could therefore be exploited by targeting it as a potential vulnerable spot in the pathogen. Here, we overexpressed an aggregation-prone segment of the P. falciparum ubiquitin transferase (PfUTf), an E3 ubiquitin ligase protein that has been previously demonstrated to regulate the stability of parasite proteins involved in invasion, development and drug metabolism. Overexpression of PfUTf in P. falciparum had evident phenotypic effects observed by transmission electron microscopy and confocal fluorescence microscopy, increased endogenous protein aggregation, disrupted proteostasis, and caused significant growth impairment in the parasite. Combined with dihydroartemisinin treatment, PfUTf overexpression had a synergistic effect that further compromised the parasite´s viability, linking protein aggregation to proteasome dysfunction. Changes in the distribution of aggregation-prone proteins, shown by the altered subcellular fluorescent pattern of the new investigational aggregated protein dye and antiplasmodial compound YAT2150 in the overexpressing P. falciparum line, highlighted the critical balance between protein aggregation, stress responses, and parasite viability, suggesting proteostasis-targeting therapies as a good antimalarial strategy.

Keywords:  E3 ubiquitin ligases; Plasmodium falciparum; new antimalarial therapies; protein aggregation; proteostasis disruption

DOI:  https://doi.org/10.3389/fcimb.2025.1565814
ACS Chem Neurosci. 2025 May 27.

Mechanisms of Alpha-Synuclein-Seeded Aggregation in Neurons Revealed by Fluorescence Lifetime Imaging.

Paula-Marie E Ivey, Magaly Guzman Sosa, Abdelrahman Salem, Sehong Min, Wenzhu Qi, Alicia N Scott, Karin F K Ejendal, Tamara L Kinzer-Ursem, Jean-Christophe Rochet, Kevin J Webb.

  The brains of Parkinson's disease (PD) patients are characterized by the presence of Lewy body inclusions enriched with fibrillar forms of the presynaptic protein alpha-synuclein (aSyn). Despite related evidence that Lewy pathology spreads across different brain regions as the disease progresses, the underlying mechanism, and hence the fundamental cause of PD progression, is unknown. The propagation of aSyn pathology is thought to potentially occur through the release of aSyn aggregates from diseased neurons, their uptake by neighboring healthy neurons via endocytosis, and subsequent seeding of native aSyn aggregation in the cytosol. A critical aspect of this process is believed to involve the escape of internalized aggregates from the endolysosomal compartment, though direct evidence of this mechanism in cultured neuron models remains lacking. In this study, we utilize a custom-built, time-gated fluorescence lifetime imaging microscopy (FLIM) system to investigate the progression of seeded aggregation over time in live cortical neurons. By establishing fluorescence lifetime sensitivity to aSyn aggregation levels, we are able to monitor the protein's aggregation state. Through a FLIM analysis of neurons expressing aSyn-mVenus and exposed to aSyn preformed fibrils labeled with the acid-responsive dye pHrodo, we reveal the protein's aggregation state in both the cytosol and the endolysosomal compartment. The results indicate that aSyn seeds undergo partial disassembly prior to escaping the endocytic pathway and that this escape is closely linked to the aggregation of cytosolic aSyn. In certain neurons, monomeric aSyn is found to translocate from the cytosol into the endolysosomal compartment, where it apparently forms aggregates in proximity to retained seeds. Additional analyses reveal zones of neuritic aSyn aggregates that overlap with regions of microtubule disruption. Collectively, these findings enhance our understanding of aSyn pathology propagation in PD and other synucleinopathies, motivate additional experiments along these lines, and offer a path to guide the development of disease-modifying therapies.

Keywords:  Parkinson’s disease; alpha-synuclein; fluorescence lifetime imaging microscopy; live-cell imaging; neurodegenerative diseases; protein aggregation

DOI:  https://doi.org/10.1021/acschemneuro.5c00236
ACS Chem Neurosci. 2025 May 26.

Molecular Insight into Amyloid Fibril-Templated Aggregation of Biomarkers.

Rongfeng Zou, Hans Ågren.

  The aggregation of misfolded proteins into β-sheet-rich fibrils constitutes a characteristic feature of neurodegenerative disorders and represents a therapeutic target. While cryo-electron microscopy has elucidated ordered binding patterns of small molecules on fibril surfaces, the mechanisms of ordered aggregate formation generally remain unclear. This study employs molecular dynamics (MD) simulations of the model ligand GTP-1 to examine fibril-templated ligand aggregation and elucidate the molecular determinants governing the aggregation process. Our results showed that in aqueous solution, GTP-1 molecules form dynamic clusters without preferential configurations, whereas tau fibril surfaces induce organized aggregation through protein-ligand hydrogen bonding and ligand-ligand π-π stacking interactions. 1000 independent 100 ns simulations were initiated from diverse ligand conformations to comprehensively sample the conformational landscape. Analysis of the MD trajectories revealed two distinct aggregation pathways. Starting from random initial configurations, on-pathway trajectories spontaneously sampled crystal-structure-like conformations during the simulation, and these conformations exhibited high kinetic stability after formation. In contrast, off-pathway trajectories were characterized by ligands adopting non-native binding geometries, with continuous interconversions between multiple disordered states. The conformational stability of on-pathway states was attributed to optimal surface complementarity and enhanced intermolecular interactions, while off-pathway configurations exhibited reduced structural order and increased conformational flexibility. Quantitative analysis demonstrated differential hydrogen-bonding patterns, with on-pathway aggregates forming 2.01 bonds per structure compared to 0.74 in off-pathway configurations. Energy decomposition identified protein-ligand interactions as the primary determinant of binding energetics, highlighting the direct influence of fibril surface properties on ligand aggregation. These findings provide a mechanistic basis for fibril-templated aggregation and offer a rational foundation for designing diagnostic agents targeting pathological protein fibrils in neurodegenerative diseases.

Keywords:  fibril-templated aggregation; ligand aggregation; molecular dynamics; neurodegenerative disorders; tau fibril

DOI:  https://doi.org/10.1021/acschemneuro.5c00103