bims-proned 2025-09-07 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–09–07
twenty-six papers selected by
Verena Kohler, Umeå University

Diosgenin reduces β-sheet content in mutated α-syn aggregation: Insights from conformational dynamics at intracellular and extracellular neuronal salt concentrations.
De novo design of protein binders to stabilize monomeric TDP-43 and inhibit its pathological aggregation.
Sulfonamide Inhibitors of Amyloid Aggregation: A Promising Path against Neurodegenerative Diseases.
Adenine bolsters the monomeric conformations of the intrinsically disordered A53T mutant of α-Synuclein protein.
Multiomic Analysis Reveals Molecular Pathways Associated with Intestinal Aggregation of α-Synuclein.
Recruitment of Aβ into α‑Synuclein Condensates Catalyzes Primary Nucleation of α‑Synuclein Aggregation.
The Proteostasis Network in Proteinopathies: Mechanisms and Interconnections.
The aging factor EPS8 induces disease-related protein aggregation through RAC signaling hyperactivation.
Astrocyte Autophagy in Neurodegenerative Diseases: Current Progress in Mechanisms and Therapeutics.
Cellular fibronectin exacerbates α-synuclein aggregation via integrin alpha4beta1 mediated PARP1 and SCD elevation.
Concentration-Dependent Mutational Scanning Probes the Cellular Folding Landscape of α -Synuclein in Yeast.
Differential Effects on In Vitro Tau Aggregation Due to 7, 11, and 14 Pseudophosphorylated Sites.
Sequestering sequestosome 1 via S-acylation in autophagy, Huntington disease, and beyond.
Mitochondrial protein import stress augments α-synuclein aggregation and neural damage independent of bioenergetics.
Polyserine-mediated targeting of FAF2/UBXD8 ameliorates tau aggregation.
Amyloid β interaction with membranes: Removal of cholesterol from the membranes to catalyze aggregation and amyloid pathology.
On the self-assembly of αB-crystallin.
TDP-43-immunity-microbiota axis in amyotrophic lateral sclerosis: A potential pathogenic mechanism.
HSP-1-Specific Nanobodies Alter Chaperone Function in vitro and in vivo.
Lysine-Targeting Inhibitors of Amyloidogenic Protein Aggregation: A Promise for Neurodegenerative Proteinopathies.
Role of Netrin-1 dysregulation in early neuronal pathology of α-synuclein models of Parkinson's disease.
ISRIB Promotes Aggregation of TIA-1 by Modulating Its Phase Separation in Vitro.
Alpha-synuclein is increased in erythrocytes in parkinson's disease cases.
PolyQ-expansion of Ataxin-2 disrupts microtubule stability and impairs axon outgrowth.
Modified tau leads to neuronal and global ribosome dysfunction in C. elegans model of tauopathy.
Nuclear Protein Aggregates Disrupt RNA Processing and Alter Biomechanics in a Muscle Cell Model of OPMD.

J Mol Graph Model. 2025 Sep 01. pii: S1093-3263(25)00220-7. [Epub ahead of print]142 109160

Diosgenin reduces β-sheet content in mutated α-syn aggregation: Insights from conformational dynamics at intracellular and extracellular neuronal salt concentrations.

Nandeshwar, Umakanta Tripathy.

  Parkinson's disease (PD) is marked by the aggregation of α-syn protein and its mutant forms, such as A30P, A53T, and E46K, which make the protein more prone to misfolding and aggregation, leading to neuronal cell death. This study explores the potential of Diosgenin, a phytoconstituent identified through ADMET predictions, to inhibit α-syn aggregation at both extracellular (0.145 M) and intracellular (0.015 M) salt concentrations. Molecular dynamics (MD) simulation revealed that Diosgenin stabilizes α-syn mutants by inducing conformational changes that reduce β-sheet content, a key factor in aggregation. The salt concentration influenced the structural dynamics, with higher salt levels generally promoting more compact and stable conformations. Principal component analysis (PCA) and free energy landscapes further confirmed the enhanced stability of the Diosgenin-bound α-syn mutants. The outcomes of the study suggest that Diosgenin could serve as a promising therapeutic agent for mitigating PD progression by targeting the aggregation of α-syn mutants and reducing its β-sheet content at intracellular and extracellular neuronal salt concentration.

Keywords:  Diosgenin; MD simulation; Molecular docking; Natural molecules; Parkinson's Disease (PD); α-synuclein

DOI:  https://doi.org/10.1016/j.jmgm.2025.109160
Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2505320122

De novo design of protein binders to stabilize monomeric TDP-43 and inhibit its pathological aggregation.

Gangyu Sun, Xiang Li, Jiaojiao Hu, Tianbin Yang, Cong Liu, Zhizhi Wang, Dan Li, Wenqing Xu.

  Pathological aggregation of transactive response DNA binding protein of 43 kDa (TDP-43), primarily driven by its low-complexity domain, is closely associated with various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite the therapeutic potential of preventing TDP-43 aggregation, no effective small molecule or biomacromolecule therapeutics have been successfully developed so far. Here, we introduce a protein design strategy that yields de novo designed proteins capable of stabilizing the key amyloidogenic region of TDP-43 in its native helical conformation with nanomolar binding affinity. The binding mechanism was further characterized by the NMR and mutagenesis study. More importantly, we demonstrated that our designed protein binders efficiently reduced TDP-43 amyloid aggregation both in vitro and in cells. Our work provides a strategy for designing protein stabilizer of the native conformation of pathological proteins for preventing its amyloid aggregation, shedding light on the development of potential therapeutic approaches for ALS, FTLD, and other protein aggregation-associated diseases.

Keywords:  TDP-43; neural degenerative disease; protein design

DOI:  https://doi.org/10.1073/pnas.2505320122
ChemMedChem. 2025 Sep 01. e202500324

Sulfonamide Inhibitors of Amyloid Aggregation: A Promising Path against Neurodegenerative Diseases.

Joana Smirnovienė, Daumantas Matulis.

  Protein amyloid aggregation is a critical pathological process implicated in nearly 50 amyloid-related diseases, including Alzheimer's and Parkinson's diseases. This review highlights the potential of sulfonamides, a versatile class of compounds recognized for their diverse pharmacological properties, as modulators of protein aggregation. We provide an overview of studies examining the efficacy of sulfonamide derivatives in inhibiting the aggregation of various amyloidogenic proteins, including amyloid-beta, tau, alpha-synuclein, insulin, and transthyretin. In vitro assays, such as Thioflavin T fluorescence and high-resolution imaging techniques, have shown that certain sulfonamides can significantly inhibit fibril formation and promote the stabilization of non-aggregated protein states. The potential for sulfonamides to serve as multi-target agents offers new avenues for therapeutic development. By integrating findings from current research, we support a proposal that sulfonamide-based compounds could play a pivotal role in addressing the multifaceted nature of amyloid-related neurodegenerative diseases, paving the way for innovative therapeutic strategies.

Keywords:  Alzheimer's disease; alpha‐synuclein; amyloid beta‐peptides; protein aggregation; sulfonamides

DOI:  https://doi.org/10.1002/cmdc.202500324
Comput Biol Chem. 2025 Aug 26. pii: S1476-9271(25)00322-6. [Epub ahead of print]120(Pt 1): 108661

Adenine bolsters the monomeric conformations of the intrinsically disordered A53T mutant of α-Synuclein protein.

Payal Singh, Almas Akhtar, Nikita Admane, Abhinav Grover.

  Parkinson's disease (PD) is significantly characterized by the accumulation of α-synuclein (α-Syn) amyloid aggregates, especially in the form of Lewy bodies. Our study explores the effect of one of the four nucleobases, adenine, on the amyloid transformation of the A53T mutant of α-Syn (A53T Syn), which is linked to the early-onset PD characterized by increased protofibril production and fast aggregation. Systematic analysis using biophysical techniques in conjunction with computational methods demonstrated that adenine stabilizes the monomeric conformations of A53T Syn by interacting with the NAC domain of the protein through non-covalent interactions. Adenine specifically prevents the amyloid transformation of the intrinsically disordered A53T Syn protein and has no effect on the fibrillation of the wild type α-Syn protein. Replica exchange molecular dynamics (REMD) simulations established that adenine decreases the tendency of A53T Syn to form amyloid aggregates by reducing intramolecular hydrogen bonds and abrogating malicious structural transitions into β-sheet rich conformations. This decrease in β-sheet rich conformations is also corroborated by nearly 85 % decrease in Thioflavin T binding at the saturation phase of amyloid transformation kinetics. Adenine stabilizes the monomeric conformations of A53T Syn, preventing the formation of cross-β amyloids. Through several morphological investigations employing TEM, AFM, and particle size distribution analysis by DLS, we validated the amyloid-modulatory effects of adenine. Our findings collectively demonstrate that adenine shows a selective efficacy against A53T Syn and poses as a good therapeutic candidate for early-onset PD. Further investigations on adenine using cellular and animal models can support early intervention strategies and possible treatments.

Keywords:  A53T; Adenine; Biophysical Characterization; In-silico Screening; Protein Aggregation; REMD Simulation; α-synuclein

DOI:  https://doi.org/10.1016/j.compbiolchem.2025.108661
bioRxiv. 2025 Aug 30. pii: 2025.08.27.672706. [Epub ahead of print]

Multiomic Analysis Reveals Molecular Pathways Associated with Intestinal Aggregation of α-Synuclein.

Julia M Balsamo, Ying Yan, Dylan Thai, Stephanie M Cologna, Elizabeth N Bess.

Aggregates of the protein α-synuclein may initially form in the gut before propagating to the brain in Parkinson's disease. Indeed, our prior work supports that enteroendocrine cells, specialized intestinal epithelial cells, could play a key role in the development of this disease. Enteroendocrine cells natively express α-synuclein and synapse with enteric neurons as well as the vagus nerve. Severing the vagus nerve reduces the load of α-synuclein aggregates in the brain, suggesting that this nerve is a conduit for gut-to-brain spread. Enteroendocrine cells line the gut lumen, as such, they are in constant contact with metabolites of the gut microbiota. We previously found that when enteroendocrine cells are exposed to nitrite-a potent oxidant produced by gut bacterial Enterobacteriaceae -a biochemical pathway is initiated that results in α-synuclein aggregation. Here, we determined that dopamine production is critical to this mechanism of nitrite-induced α-synuclein aggregation. Using enteroendocrine cells, we modulated dopamine biosynthesis and profiled the cellular proteome and lipidome. Proteomic signatures in dopamine-free cells were distinctly different than in enteroendocrine cells, highlighting pathways relevant to intestinal development of Parkinson's disease. Intriguingly, we observed that enteroendocrine cells maintain viability upon exposure to nitrite and in the presence of α-synuclein aggregates. This cellular robustness suggests that dopamine-producing enteroendocrine cells may be a reservoir of toxic α-synuclein aggregates, which can spread through a prion-like process. As a possible antidote, our findings show that benserazide-a chemical inhibitor of dopamine biosynthesis-limits formation of these aggregates in enteroendocrine cells. These studies lay a foundation for mechanistically informed therapeutic targets to prevent intestinal formation of α-synuclein aggregates before they spread to the brain.
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DOI: https://doi.org/10.1101/2025.08.27.672706
ACS Cent Sci. 2025 Aug 27. 11(8): 1481-1491

Recruitment of Aβ into α‑Synuclein Condensates Catalyzes Primary Nucleation of α‑Synuclein Aggregation.

Owen M Morris, Alexander Röntgen, Zenon Toprakcioglu, Mariana Cali, Samuel Dada, Michele Vendruscolo.

The aggregation of amyloid-β (Aβ) and α-synuclein (αSyn) is linked to Alzheimer's and Parkinson's diseases, with growing evidence suggesting possible interactions between Aβ and αSyn in the pathology of these neurodegenerative conditions. In this context, the recent observation that protein aggregation into amyloid fibrils may take place within liquid condensates generated through liquid-liquid phase separation prompts the question of how amyloidogenic proteins interact with each other, and more specifically whether Aβ can influence the overall phase behavior of αSyn or vice versa. To address this question, we investigated the interplay between Aβ40, the most abundant form of Aβ, with αSyn. We found that monomeric Aβ40 is sequestered into αSyn condensates, where it enhances heterogeneous primary nucleation, and accelerates the aggregation of αSyn within the liquid condensates. Using a chemical kinetics framework, we further showed that this liquid-to-solid transition is not significantly affected by adding preformed Aβ40 fibrillar seeds, further indicating that monomeric Aβ40 specifically enhances the primary nucleation of αSyn within the condensed phase. These findings identify some of the key mechanistic processes underlying amyloid aggregation within liquid condensates, prompting further investigations into the possible role of Aβ and αSyn cocondensation interactions in the onset and progression of neurodegenerative disorders.

DOI: https://doi.org/10.1021/acscentsci.5c00614
Am J Pathol. 2025 Aug 26. pii: S0002-9440(25)00300-1. [Epub ahead of print]

The Proteostasis Network in Proteinopathies: Mechanisms and Interconnections.

Dariusz Pytel, Jody Fromm Longo.

  Proteinopathies are neurodegenerative disorders that are characterized by accumulation of misfolded toxic protein aggregates that lead to synaptic and neuronal dysfunction. Though genetically, clinically and pathologically distinct, a common feature of these diseases is disruption of protein homeostasis (proteostasis), which causes accumulation of misfolded proteins. The machinery mediating proteostasis exquisitely balances and interlaces protein synthesis, protein folding and trafficking, and protein degradation processes within the proteostasis network to maintain homeostasis. The proteostasis network governs a functional and dynamic proteome by modulating the timing, location, and stoichiometry of protein expression, surveillance and maintenance of protein folding and removal of misfolded or excess proteins. Although a functional proteome is essential for the health of all cell types, this is especially true for neurons which are prone to enhanced cellular stress. Aging is the most important risk factor for proteostasis decline and the development of proteinopathies. However, germline and somatic mutations can also functionally impair components of the proteostasis network. Post-mitotic cells, particularly neurons, are rendered further susceptible to proteostasis dysfunction due to their extended lifespan. This review discusses the interconnections between the functional components mediating proteostasis in neuronal cells and how aberrations in proteostasis contribute to neuronal dysfunction and disease.

Keywords:  Alzheimer’s Disease; Amyotrophic Lateral Sclerosis; ER stress; ERAD; Frontotemporal Dementia; Huntington’s Disease; Parkinson’s Disease; UPR; aggregates; autophagy; protein homeostasis; proteinopathies

DOI:  https://doi.org/10.1016/j.ajpath.2025.07.011
Nat Aging. 2025 Sep 03.

The aging factor EPS8 induces disease-related protein aggregation through RAC signaling hyperactivation.

Seda Koyuncu, Yaiza Dominguez-Canterla, Rafael Alis, Nassima Salarzai, Dunja Petrovic, Nuria Flames, David Vilchez.

Aging is a major risk factor for neurodegenerative diseases associated with protein aggregation, including Huntington's disease and amyotrophic lateral sclerosis (ALS). Although these diseases involve different aggregation-prone proteins, their common late onset suggests a link to converging changes resulting from aging. In this study, we found that age-associated hyperactivation of EPS8/RAC signaling in Caenorhabditis elegans promotes the pathological aggregation of Huntington's disease-related polyglutamine repeats and ALS-associated mutant FUS and TDP-43 variants. Conversely, knockdown of eps-8 or RAC orthologs prevents protein aggregation and subsequent deficits in neuronal function during aging. Similarly, inhibiting EPS8 signaling reduces protein aggregation and neurodegeneration in human cell models. We further identify the deubiquitinating enzyme USP4 as a regulator of EPS8 ubiquitination and degradation in both worms and human cells. Notably, reducing USP-4 upregulation during aging prevents EPS-8 accumulation, extends longevity and attenuates disease-related changes. Our findings suggest that targeting EPS8 and its regulatory mechanisms could provide therapeutic strategies for age-related diseases.

DOI: https://doi.org/10.1038/s43587-025-00943-w
Neurochem Res. 2025 Sep 05. 50(5): 287

Astrocyte Autophagy in Neurodegenerative Diseases: Current Progress in Mechanisms and Therapeutics.

Jialei Qian, Shengyuan Ren, Tianning Ren, Renke Shi, Liang Qiao, Jing Kang.

  Astrocytes, the most abundant and functionally diverse glial cell type in the brain, play a crucial role in maintaining cellular homeostasis and promoting neuronal survival. Autophagy is the process of transferring senescent, denatured, or damaged proteins and organelles from cells to lysosomes for degradation. However, recent research on autophagy in the central nervous system has focused on neurons. In this paper, we reviewed the latest findings on astrocyte autophagy and its mechanisms in regulating neurodegenerative disorders. It influences the pathological processes of Alzheimer's disease, Parkinson's disease, Huntington's disease, and other synucleinopathies (including dementia with Lewy bodies and Parkinson's disease dementia) by regulating oxidative stress and inflammatory responses, as well as aberrant protein aggregation and folding. Furthermore, we listed medications that can prevent or treat neurodegenerative disorders by modulating astrocyte autophagy pathways, providing new insights into preventive and therapeutic strategies for neurodegenerative diseases.

Keywords:  Astrocytes; Autophagy; Mechanism; Neurodegenerative disorders; Treatment

DOI:  https://doi.org/10.1007/s11064-025-04532-6
Neurotherapeutics. 2025 Sep 04. pii: S1878-7479(25)00207-7. [Epub ahead of print] e00729

Cellular fibronectin exacerbates α-synuclein aggregation via integrin alpha4beta1 mediated PARP1 and SCD elevation.

Zifeng Huang, Hui Zhong, Yingqiong Lu, Ruoyang Yu, Muwei Zhang, Jialing Zheng, Bin Xiao, Zhidong Zhou, Yinghua Yu, Chao Deng, Kunlin Jin, Shuzhen Zhu, Chong Li, Xiaoying Cui, Karolina Poplawska-Domaszewicz, K Ray Chaudhuri, Eng-King Tan, Qing Wang.

  Mitochondrial dysfunction and lipid metabolic disturbance may promote pathologic α-synuclein (α-syn) aggregation, accelerating the progression of Parkinson's disease (PD). Whether extracellular matrices are associated with those pathological mechanisms in PD remains elusive. Here, we aimed to identify if cellular fibronectin (cFn), a component of extracellular matrices, contributes to α-syn abnormality via inducing mitochondrial energy depletion or disrupting lipid homeostasis. In Our study, 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP)-treated PD mice and human neuronal SH-SY5Y cells were used. Astrocyte-derived cFn protein delivery and AAV-mediated cFn knockdown mouse models were established to validate the functional role of cFn. Mitochondrial dysfunction was detected by transmission electron microscopy (TEM), and the level of poly (ADP‒ribose) (PAR) polymerase-1(PARP1), pathologic α-syn and cFn-induced lipid dysmetabolism was determined. We demonstrated that excessive cFn accumulated in the SNpc of MPTP-treated mice, and cFn rather than plasma Fn (pFn) exacerbated neuronal mitochondrial dysfunction and α-syn accumulation. Mechanically, cFn induced PARP1 activation via integrin α4β1, which contributed to neuronal NAD + depletion and pathologic α-syn aggregation. Furthermore, cFn induced an increase in free fatty acids (FAs) and triglycerides (TAG) in neurons by binding to integrin α4β1, which synergistically contributed to α-syn abnormality. We revealed that cFn induced stearoyl-CoA desaturase (SCD) activation via integrin α4β1, which was interacted with SCD. Genetically depleting cFn suppressed PARP1 activation and SCD elevation, which further rescued the mitochondrial disruption and α-syn abnormalities in MPTP-treated mice. Overall, our findings suggest that cFn exacerbates α-syn aggregation via integrin α4β1-mediated PARP1 and SCD elevation. cFn-targeting therapy may be a promising strategy for treating PD.

Keywords:  Fibronectin; Mitochondrial dysfunction; Parkinson's disease; Poly (ADP‒ribose) (PAR) polymerase-1; Stearoyl-CoA desaturase; α-Synuclein

DOI:  https://doi.org/10.1016/j.neurot.2025.e00729
bioRxiv. 2025 Aug 30. pii: 2025.08.29.672156. [Epub ahead of print]

Concentration-Dependent Mutational Scanning Probes the Cellular Folding Landscape of α -Synuclein in Yeast.

Daeun Noh, Robert W Newberry.

The misfolding and aggregation of α-synuclein is a central molecular event in the etiology of Parkinson's disease and related disorders. α-Synuclein misfolding and pathology are both concentration-dependent, but it is not clear precisely how changes in concentration alter the folding landscape within cells. Whereas most conventional structural biology approaches offer limited resolution in living systems, deep mutational scanning can offer insight into the folding state of a protein in living cells, and we apply this method to probe concentration-dependent changes in the folding of α-synuclein in a popular yeast model of pathology. We discover that at a wide range of cellular concentrations, α-synuclein is highly biased toward formation of a membrane-bound amphiphilic helix that imparts toxicity. Population of this toxic state can be disrupted by mutations that reduce membrane affinity, which shift the folding equilibrium away from the membrane-bound state. Reduced-affinity variants exhibit distinct sensitivity to concentration relative to variants with WT-like affinity, likely because these variants are expressed at concentrations closer to their dissociation constant for membrane binding. These results show how mutational scanning can provide high-resolution insights into the folding landscape of proteins in living cells, which is likely to be of special utility for studying proteins that misfolding and/or aggregate.
Impact Statement: Protein misfolding is often concentration-dependent, but studying concentration-dependent changes in folding in living cells is challenging. By using high-throughput mutagenesis, we reveal changes in the population of toxic conformations of the Parkinson's-associated protein α-synuclein. We discover that in a yeast model of pathology, α-synuclein is highly biased toward membrane binding, which in turn disrupts cellular homeostasis.

DOI: https://doi.org/10.1101/2025.08.29.672156
Biochemistry. 2025 Aug 30.

Differential Effects on In Vitro Tau Aggregation Due to 7, 11, and 14 Pseudophosphorylated Sites.

Veena Prasad, Truman C Gamblin.

Neurofibrillary tangles are intracellular aggregates composed of the microtubule-associated protein tau. These insoluble aggregates are found in the brain of those affected by Alzheimer's disease and other related tauopathies. Hyperphosphorylation of tau in disease has been hypothesized to cause tau to dissociate from microtubules and form amyloid-like oligomers and fibrils. Under normal conditions, there is 2-3 mol of phosphate per mole of tau; however, studies have found 2-3 times more phosphate per mole of tau in diseased conditions. The in vitro arachidonic acid induction of aggregation of different combinations of pseudophosphorylated sites up to 7 sites has previously been shown to result in differences in aggregation properties, characterized by increasing lengths of filaments with increasing numbers of pseudophosphorylation sites. Because several other sites of tau are also phosphorylated in disease, tau aggregation of protein variants with 11 and 14 sites mimicking hyperphosphorylation was compared to the 7 pseudophosphorylation sites previously studied using arachidonic acid and polyphosphate as fibrillization inducers. An increase in filament length, along with a decrease in the number of shorter filaments, was observed with increasing numbers of pseudophosphorylation sites regardless of the inducer employed. Variants displayed differential aggregation kinetics depending on the number of pseudophosphorylation sites and the inducer used. Although the rate of tubulin polymerization decreased as the number of pseudophosphorylation sites increased, microtubule stability was maintained across all pseudophosphorylated variants compared with unmodified wild-type tau. These results demonstrate that increasing levels of hyperphosphorylation can continue to have increased effects on tau aggregation and microtubule stabilization.

DOI: https://doi.org/10.1021/acs.biochem.5c00358
Autophagy Rep. 2025 ;4(1): 2547975

Sequestering sequestosome 1 via S-acylation in autophagy, Huntington disease, and beyond.

Y Alshehabi, F Abrar, D D O Martin.

  Protein mislocalization and aggregation are hallmark features in neurodegeneration. As proteins mislocalize, proteostasis deficiency and protein aggregation typically follow. Autophagy is a crucial pathway for the removal of protein aggregates to maintain neuronal health, but is impaired in various neurodegenerative diseases, including Huntington disease (HD). We identified S-acylation, a reversible lipid modification of proteins, as an important regulator in protein trafficking and autophagy. SQSTM1 (sequestosome 1/p62) is an essential selective autophagy receptor for the sequestration of ubiquitinated cargoes within autophagosomes and subsequent delivery into lysosomes for degradation. Recently, we reported that S-acylation of SQSTM1 at the di-cysteine motif C289,290 directs SQSTM1 to lysosomes. We further showed that SQSTM1 S-acylation is significantly reduced in brains from both HD patients and mouse HD model, which may result in the cargo sequestration defect within autophagosomes in HD. Treatment with palmostatin B, a deacylation inhibitor, significantly increases SQSTM1 localization to lysosomes. Our work highlights SQSTM1 S-acylation as a novel potential therapeutic strategy in HD. As a crucial autophagy component, our work suggests S-acylation of SQSTM1 may have a broader role in neurodegeneration.

Keywords:  Autophagy; Huntington disease; S-acylation; fasting; huntingtin; localization; mouse model; palmitoylation; palmostatin B; sequestosome 1

DOI:  https://doi.org/10.1080/27694127.2025.2547975
Res Sq. 2025 Aug 18. pii: rs.3.rs-3136613. [Epub ahead of print]

Mitochondrial protein import stress augments α-synuclein aggregation and neural damage independent of bioenergetics.

Xin Jie Chen, Liam Coyne, Arnav Rana, Xiaowen Wang, Sanaea Bhagwagar, Yumiko Umino, Eduardo Solessio, Frank Middleton.

Genetic and environmental factors are known to converge on mitochondria to cause Parkinson's disease (PD). However, the mechanisms by which mitochondrial dysfunction contributes to neurodegeneration remain incompletely understood. Non-bioenergetic pathways of the mitochondria are increasingly appreciated, but confounding bioenergetic defects are a major barrier to experimental validation. Here, we show that mild mitochondrial protein import stress augments neural damage independent of bioenergetics. We induce protein import stress in a mouse model of PD expressing α-synuclein(A53T). The double mutant mice demonstrate increased size of α-synuclein aggregates, increased aggregation of mitochondrial preproteins, heightened neuroinflammation and worsened motor defect relative to α-synuclein(A53T) single mutants. Importantly, we found no evidence of bioenergetic defects in any of the mutant mice. These data suggest that mitochondrial protein import stress, which can be induced by many types of mitochondrial injuries, can contribute to neural damage through cytosolic proteostatic stress and possible co-aggregation of mitochondrial and neuropathogenic proteins independent of bioenergetics.

DOI: https://doi.org/10.21203/rs.3.rs-3136613/v1
Neuron. 2025 Aug 29. pii: S0896-6273(25)00587-2. [Epub ahead of print]

Polyserine-mediated targeting of FAF2/UBXD8 ameliorates tau aggregation.

Meaghan Van Alstyne, Georgia Brown, Vanessa L Nguyen, Mani Ramaswami, Charles A Hoeffer, Roy Parker.

  Tau aggregation is a hallmark of several neurodegenerative disorders, and the gain of toxic function of misfolded tau species is linked to pathobiology. Herein, we identified proteins that limit tau aggregation when targeted to tau aggregates by polyserine domains. Polyserine targeting was most effective at mitigating tau aggregation when fused to the vasolin-containing protein (VCP) adaptor protein fas-associated factor family member 2/UBX domain-containing protein 8 (FAF2/UBXD8). Surprisingly, FAF2/UBXD8 suppresses tau aggregation independent of VCP but does require ubiquitination, membrane localization, and a ubiquitin regulator X (UBX) domain. Validation in animal models demonstrated that polyserine-targeted FAF2/UBXD8 rescues tau-induced neurodegeneration in Drosophila. Further, delivery of targeted FAF2/UBXD8 reduced gliosis, seeding capacity, and insoluble tau levels in PS19 tau transgenic mice while improving contextual fear conditioning. Collectively, our findings highlight polyserine as a tau-targeting strategy and identify targeted FAF2/UBXD8 as a potent suppressor of tau pathology.

Keywords:  FAF2; UBXD8; neurodegeneration; polyserine; protein aggregation; tau; tauopathy

DOI:  https://doi.org/10.1016/j.neuron.2025.08.002
bioRxiv. 2025 Aug 24. pii: 2025.08.20.671368. [Epub ahead of print]

Amyloid β interaction with membranes: Removal of cholesterol from the membranes to catalyze aggregation and amyloid pathology.

Rishiram Baral, Ruan van Deventer, Yuri L Lyubchenko.

The interplay between the cholesterol metabolism and assembly of Aβ42 (the 42- residue form of the amyloid-β peptide) peptides in pathological aggregates is considered as one of the major molecular mechanisms in development of Alzheimer's disease (AD). Numerous in vitro studies led to the finding that the high cholesterol levels in membranes accelerate the production of Aβ aggregates. The molecular mechanisms explaining how cholesterol localized inside the membrane bilayer catalyzes the assembly of Aβ aggregates above the membrane remain unknown. We addressed this problem by combining different AFM modalities, including imaging and force spectroscopy, with fluorescence spectroscopy. Our combined studies revealed that Aβ42 was capable of removing cholesterol from the membrane. Importantly, physiologically low concentrations of Aβ42 demonstrate such ability of monomeric Aβ42. Extracted cholesterol interacts with Aβ42 and accelerates its on- membrane aggregation. We propose a model of interaction of Aβ42 with membranes based on the ability of Aβ42 to extract cholesterol, which explains several AD associated observations related to cholesterol interplay with Aβ42 aggregation resulting in the AD onset and progression.

DOI: https://doi.org/10.1101/2025.08.20.671368
Soft Matter. 2025 Sep 02.

On the self-assembly of αB-crystallin.

Ewelina Lindbladh, Marija Dubackic, Dev Thacker, Sara Linse, Ulf Olsson.

The molecular chaperone αB-crystallin is a small heat shock protein that inhibits the aggregation of, among others, Aβ42 and α-synuclein. These proteins are major hallmarks of Alzheimer's and Parkinson's disease, respectively. In order to understand the mechanism with which αB-crystallin performs its chaperone function it is essential to characterize its self-assembly in terms of aggregate size distribution, structure, and critical concentration. The size distribution of the assemblies has been widely discussed and they have been suggested to be monodisperse or polydisperse with varying size distributions covering a range of 10-40 monomers per assembly. Here, the size distribution was studied using dynamic and static light scattering, microfluidic diffusional sizing (MDS), as well as small-angle X-ray scattering (SAXS). Findings indicate that αB-crystallin has a preference toward forming spherical assemblies consisting of 18 monomers with a hydrodynamic radius of ≈7 nm after one week. SAXS data were modelled using a homogeneous sphere model with a radius of 6 nm, which is comparable to the light scattering and MDS results. 2D classes built from negative stain transmission electron microscopy images suggest that the spherical aggregates contain several smaller globular units. Furthermore, the findings show that the size of the assemblies is independent of protein concentration, supporting a strong preference for specific assembly constellations.

DOI: https://doi.org/10.1039/d5sm00684h
Neural Regen Res. 2025 Sep 03.

TDP-43-immunity-microbiota axis in amyotrophic lateral sclerosis: A potential pathogenic mechanism.

Yasmine Abbassi, Dorian Fink, Francesco Cei, Elena Niccolai, Amedeo Amedei.

   ABSTRACT: Amyotrophic lateral sclerosis is a devastating neurodegenerative disease marked by progressive motor neuron degeneration. Despite extensive research, effective treatments remain elusive, underscoring the need to explore the molecular mechanisms driving disease progression. The amyotrophic lateral sclerosis complexity is further compounded by its large heterogeneity, encompassing both genetic and sporadic forms, diverse phenotypic presentations, and highly variable progression rates. A key pathological feature of amyotrophic lateral sclerosis is the aggregation of TAR DNA-binding protein 43, which contributes to cellular toxicity, neuroinflammation, and neuronal dysfunction. This review explores the complex interplay between TAR DNA-binding protein 43 pathology, immunity dysregulation, and the gut-brain axis, with a focus on the role of microbiome-derived metabolites in amyotrophic lateral sclerosis. Neuroinflammation, mediated by both innate and adaptive immunity, plays a central role in disease pathogenesis, with TAR DNA-binding protein 43 influencing immune signaling and exacerbating neurotoxicity. Additionally, disruptions in gut microbiota composition and intestinal barrier integrity, frequently observed in amyotrophic lateral sclerosis patients, suggest a potential role for the gut-brain axis in modulating neurodegenerative processes. By integrating evidence from emerging studies, our aim is to clarify how TAR DNA-binding protein 43 aggregation contributes to neuroinflammation and immune dysfunction while exploring the gut microbiota role as both a modulator and potential biomarker of disease. Understanding these interactions could pave the way for novel therapeutic strategies, including microbiome-targeted interventions such as probiotics, dietary modifications, or immune-modulating therapies. Finally, unraveling the TAR DNA-binding protein 43-immune system-microbiome axis may offer new avenues for personalized treatments aimed at mitigating neuroinflammation, slowing amyotrophic lateral sclerosis progression, and improving patient outcomes and life quality.

Keywords:  TAR DNA-binding protein 43; amyotrophic lateral sclerosis; immunity; microbiome; neuroinflammation; short-chain fatty acids

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00440
bioRxiv. 2025 Aug 26. pii: 2025.08.25.672099. [Epub ahead of print]

HSP-1-Specific Nanobodies Alter Chaperone Function in vitro and in vivo.

Nicholas D Urban, Kunal Gharat, Zachary J Mattiola, Ashley Scheutzow, Adam Klaiss, Sarah Tabler, Asa W Huffaker, Monique Grootveld, Mary E Skinner, Janine Kirstein, Matthias C Truttmann.

Targeted regulation of 70 kilodalton Heat Shock Protein (HSP70) chaperones, particularly the essential cognate heat shock protein (HSC70) and its Caenorhabditis elegans ortholog, HSP-1, may hold the key to improving cellular proteostasis and ameliorating aging-associated conditions linked to protein misfolding and aggregation. However, tools to selectively modulate HSP70 chaperone activity remain elusive. In this study, we pioneer the development of two novel nanobodies, B12 and H5, which specifically bind to both recombinant and endogenous HSP-1. We show that these nanobodies, differing by only two amino acids in their complementarity-determining regions, bind specifically to HSP-1 and effectively reduce both HSP-1 ATPase activity and protein folding capacity in a dose-dependent manner in vitro . We further demonstrate in vivo expression of B12, but not H5, in transgenic C. elegans strains reduces heat-stress survival and proteotoxic-stress resistance, mirroring the effects of hsp-1 knockdown via RNA interference. Our findings suggest that these nanobodies can serve as effective and specific tools for modulating HSP-1 chaperone activity in vivo . These discoveries provide a foundation for future research exploring the therapeutic potential of HSP70-targeting nanobodies in aging and protein misfolding diseases.

DOI: https://doi.org/10.1101/2025.08.25.672099
JACS Au. 2025 Aug 25. 5(8): 3680-3700

Lysine-Targeting Inhibitors of Amyloidogenic Protein Aggregation: A Promise for Neurodegenerative Proteinopathies.

Kazuma Murakami, Thi Hong Van Nguyen, Chioko Nagao, Kenji Mizuguchi, Gal Bitan.

  Inhibition of amyloidogenic-protein oligomerization and aggregation is a promising therapy-development strategy for proteinopathies, such as Alzheimer's and Parkinson's diseases, in which proteins self-associate into a variety of abnormal, toxic assemblies. Despite discovery of numerous compounds modulating the self-assembly process in vitro, few have reached advanced clinical trials, and none have translated into effective therapy to date. A potential reason is a lack of clear mechanistic understanding of the interaction between the inhibitors/modulators and the target metastable protein assemblies. A unique class of compounds targets specifically Lys residues, which have been shown to be important mediators of many amyloidogenic-protein aberrant self-assembly processes due to their participation in both electrostatic and hydrophobic interactions. Although seemingly paradoxical, as these compounds do not target a specific protein, compounds targeting Lys show a remarkable ability to selectively disrupt the interactions mediating abnormal protein self-assembly. Such compounds include covalent and noncovalent Lys-binding small molecules, as well as agents controlling Lys-post-translational modification (PTM). Recent advances in this area show that the application of Lys-targeting inhibitors in antiamyloid drug discovery campaigns and Lys-reactive rational-design approaches have led to intriguing results in multiple systems, including animal models of various proteinopathies. As this strategy is applicable and promising for targeting most of the proteins involved in proteinopathies, including amyloid β-protein, tau, and α-synuclein, here we highlight Lys-binding inhibitors of abnormal protein self-assembly leading to preclinical therapeutic applications for the central nervous system.

Keywords:  Alzheimer’s disease; NMR; Parkinson’s disease; amyloid; covalent drug; mass spectrometry; post-translational modification; tauopathy

DOI:  https://doi.org/10.1021/jacsau.5c00269
J Adv Res. 2025 Sep 04. pii: S2090-1232(25)00676-9. [Epub ahead of print]

Role of Netrin-1 dysregulation in early neuronal pathology of α-synuclein models of Parkinson's disease.

Wenjing Han, Tiantian Wang, Ningping Tan, Haixin Liu, Peicheng He, Ye Hua, Yi Fan.

   INTRODUCTION: Parkinson's disease (PD) is characterized by early synaptic and axonal dysfunction, driven by α-synuclein (α-Syn, encoded by the SNCA gene) aggregation. The axon guidance molecules play critical roles in neuronal integrity, yet their dysregulation in PD remains underexplored.
OBJECTIVES: This study aimed to demonstrate how α-Syn preformed fibrils (PFFs) alter the expression of axon guidance molecules, contributing to early synucleinopathy, and to evaluate the therapeutic potential of netrin-1 (NTN1).
METHODS: Transgenic hSNCANestin mice and PFF-injected models were used. Behavioral assessments, Western blot analyses, and immunofluorescence quantified the expression of axon guidance molecules and neuronal morphology at multiple time points.
RESULTS: In hSNCANestin mice, NTN1 mRNA and protein levels decreased significantly at 8 months, while deleted in colorectal cancer (DCC) increased, correlating with reduced dendritic length, spine density, and synaptic proteins. PFF-injected mice showed similar NTN1 reduction and DCC elevation at 6 months, alongside motor deficits and tyrosine hydroxylase-positive (TH+) neuron loss. Exogenous NTN1 application reversed morphological deficits in SH-SY5Y cells and primary neurons exposed to α-Syn PFFs, highlighting its protective role.
CONCLUSION: α-Syn-induced NTN1 reduction exacerbates early PD pathology by impairing axonal and synaptic integrity, while NTN1 restoration mitigates these effects, suggesting therapeutic potential. These findings emphasize axon guidance pathways as key contributors to PD pathogenesis and targets for disease-modifying strategies.

Keywords:  Deleted in colorectal cancer; Netrin-1; Neurodegeneration; Parkinson’s disease; Synucleinopathy; α-synuclein

DOI:  https://doi.org/10.1016/j.jare.2025.08.061
Biol Pharm Bull. 2025 ;48(8): 1277-1284

ISRIB Promotes Aggregation of TIA-1 by Modulating Its Phase Separation in Vitro.

Miyu Murata, Hitomi Kimura, Shin-Ichi Tate, Kyota Yasuda.

  Stress granules (SGs) are non-membranous biomolecular condensates formed through liquid-liquid phase separation (LLPS) of RNA-binding proteins (RBPs) and RNA under stress conditions. T-cell intracellular antigen-1 (TIA-1), a major RBP of SGs, can undergo LLPS via its low-complexity domain, contributing to SG nucleation. Integrated stress response inhibitor (ISRIB), a small molecule that enhances eIF2B activity and inhibits the integrated stress response, has been widely studied for its therapeutic potential in neurodegenerative diseases. However, little is known about how ISRIB directly affects the behavior of SG proteins. Here, we show that ISRIB enhances TIA-1 phase separation and promotes its aggregation in vitro. Interestingly, this effect was mitigated in the presence of RNA or cell lysates, suggesting that RNA-binding plays a protective role against ISRIB-induced aggregation. These findings imply that ISRIB alters the physical properties of SGs in an RNA-dependent manner, raising important considerations for their therapeutic application.

Keywords:  RNA-binding protein; T-cell intracellular antigen-1; aggregation; integrated stress response inhibitor; liquid–liquid phase separation; stress granule

DOI:  https://doi.org/10.1248/bpb.b25-00294
Sci Rep. 2025 Aug 29. 15(1): 31837

Alpha-synuclein is increased in erythrocytes in parkinson's disease cases.

Ryan N Coyle, Anne M Roberts, Malcolm Horne, Christopher Fowler, Colin L Masters, Blaine R Roberts.

  Idiopathic Parkinson's disease (iPD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). Mutations in the SCNA gene, which encodes the protein alpha synuclein (α-syn), are associated with familial forms of Parkinson's disease (PD). Additionally, Lewy bodies (LBs) rich in α-synuclein are a hallmark of idiopathic Parkinson's disease (iPD) pathology. Unlike AD, there are no effective blood-based diagnostic assays for iPD. Recent studies show that measures of misfolded α-syn in cerebrospinal fluid (CSF) and skin biopsies reflect the diagnosis of iPD. The presence of misfolded α-syn suggests that the altered cellular processes in the brain that lead to aggregated α-syn may also occur in the periphery. However, CSF and skin biopsies are intrusive, highlighting the need for a blood-based diagnostic assay. Erythrocytes are the richest source of α-syn in the body, and we hypothesized that peripheral α-syn changes could be detected in erythrocytes in iPD. To test this hypothesis, we used a targeted liquid chromatography-mass spectrometry (LC-MS) assay, that included 15N-enriched recombinant α-syn as an internal standard. We compared the levels of α-syn in erythrocytes from iPD patients, AD patients, and healthy controls (CN). α-syn concentrations were significantly elevated in iPD (48.1 (29.7) µg mL-1 of erythrocytes, median (IQR)) compared to CN (36.1 (28.4) µg mL-1) and no difference was observed in AD (33.5 (18.1) µg mL-1). Although α-syn levels were significantly elevated in iPD, the receiver operating characteristic (ROC) analysis yielded an area under the curve (AUC) of 0.62, indicating that erythrocytic α-syn levels alone are not sufficient for diagnostic purposes.

Keywords:  Alpha synuclein; Erythrocytes; Parkinson’s disease; Proteomics; QQQ; Red blood cells

DOI:  https://doi.org/10.1038/s41598-025-11979-8
J Neurosci. 2025 Sep 04. pii: e0682252025. [Epub ahead of print]

PolyQ-expansion of Ataxin-2 disrupts microtubule stability and impairs axon outgrowth.

Sun K Kim, Vladimir I Gelfand.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by mislocalization and aggregation of proteins in motor neurons. Ataxin-2 (ATXN2), an RNA-binding protein harboring 22-polyglutamine (polyQ) repeats, is a risk factor for ALS, when its polyQ repeats are expanded to 27-33 repeats. However, the physiological function of ATXN2 beyond its role in RNA regulation, and how polyQ expansion in ATXN2 increases risk for ALS, remain unclear. We previously demonstrated that Drosophila Atx2 functions as a regulator of microtubule (MT) dynamics in motor neurons. Here, we uncover the molecular mechanism underlying Atx2-mediated MT regulation and how polyQ expansion disrupts its function, using a mixed-sex population of Drosophila as a model system. Specifically, we show that Atx2 requires its RNA-binding Lsm domain to regulate MTs. Notably, the LSM domains of human ATXN2 rescue MT phenotype in Drosophila, demonstrating an evolutionarily conserved role of ATXN2 in MT regulation. Importantly, we find that polyQ-expanded ATXN2 forms cytoplasmic aggregates and leads to excessive MT destabilization. Additionally, polyQ expansion severely impairs axon outgrowth. Finally, we identify Uncoordinated-76 (UNC-76/FEZ1) as a downstream effector of Atx2 in MT regulation and neuronal development.Significance Statement ALS is a progressive neurodegenerative disease with no effective treatment. Although polyglutamine (polyQ) expansion in the RNA-binding protein ATXN2 is a known risk factor for ALS, its mechanistic role in ALS pathogenesis has remained unclear. We demonstrate that ATXN2 regulates MT dynamics via its RNA-binding domain, and this role is evolutionarily conserved between Drosophila and humans. We further identify UNC-76/FEZ1 as a downstream effector of ATXN2 in regulating MT dynamics and neuronal development. Importantly, this study reveals how polyQ expansion in ATXN2 disrupts MT stability and axon growth, proposing a mechanism that may contribute to increased ALS risk.

DOI: https://doi.org/10.1523/JNEUROSCI.0682-25.2025
bioRxiv. 2025 Aug 30. pii: 2025.08.29.670302. [Epub ahead of print]

Modified tau leads to neuronal and global ribosome dysfunction in C. elegans model of tauopathy.

Atalay Ata, Hannah M Somers, Noah Lind, Jeremy H Fuqua, Jarod A Rollins.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by an early loss of memory formation which requires protein synthesis. Tau is an intrinsically disordered protein and is subject to extensive post-translational modifications (PTMs). Some PTMs have been shown to alter localization of tau and allow tau to disrupt protein translation. Protein interactome studies indicate that tau might interact with ribosomal proteins. Therefore, we hypothesized that tau is causing ribosomal dysfunction as an early event and this interaction is dependent on tau's PTMs. To test this, we used a C. elegans strain expressing single copy insertion of human tau as well as two of the most frequent modified versions of tau in mechanosensory neurons. With our assay to measure translation, we showed that in our T231 phosphorylation mimetic strain, there was a significant decrease in neuronal translation. This mimetic strain also showed a significant decrease in median lifespan and locomotion. Unexpectedly, in all our Tau-expressing strains, we detected a significant decrease in whole worm translation, suggesting a possible role of tau to influence translation in other tissues in worm. Our in vitro , in vivo and ex vivo efforts to demonstrate tau-ribosome association via fluorescent polysome profiling have shown that there is no direct association between tau and the ribosome. Ribosome dysfunction caused by modified tau could be an early event in AD pathology before the pathological hallmarks appear.

DOI: https://doi.org/10.1101/2025.08.29.670302
Aging Dis. 2025 Aug 28.

Nuclear Protein Aggregates Disrupt RNA Processing and Alter Biomechanics in a Muscle Cell Model of OPMD.

Milad Shademan, Sarah Flannery, Erik Bos, Tom M J Evers, Vahid Sheikhhassani, Alireza Mashaghi, Benno Kusters, Baziel van Engelen, Thom T Sharp, Roman Fischer, Benedikt M Kessler, Vered Raz.

Aggregation of RNA-binding proteins (RBPs) is a hallmark of several age-related neuromuscular diseases. However, our understanding of how these aggregates drive dysfunction is often limited by the use of non-disease-relevant models. Oculopharyngeal muscular dystrophy (OPMD) is caused by a short alanine expansion mutation in the PABPN1 gene, which leads to nuclear aggregation of the protein. To investigate how these aggregates impair muscle cell function, we developed a muscle cell model with inducible expression of the pathogenic PABPN1 (A16) variant and confirmed its relevance to OPMD. Using subcellular fractionation combined with mass spectrometry and RNA sequencing, we examined the molecular consequences of nuclear PABPN1 aggregation. In the cytoplasmic fraction, we observed significant impairments in cellular metabolism and biomechanics. In the nuclear fraction, RNA metabolism was broadly disrupted, and additional RBPs were significantly enriched in insoluble aggregates. Importantly, mRNAs trapped within the aggregates were associated with impaired nuclear export and decreased translation efficiency, and the pathogenic PABPN1 variant led to reduced endogenous PABPN1 levels. Our findings support a model in which OPMD pathology arises from reduced levels of soluble PABPN1 due to nuclear aggregation and establish a mechanistic link between RBP aggregation and muscle cell dysfunction, highlighting shared pathological pathways across neuromuscular and neurodegenerative diseases.

DOI: https://doi.org/10.14336/AD.2025.0699