bims-proned 2025-11-30 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–11–30
27 papers selected by
Verena Kohler, Umeå University

Small molecule inhibitors targeting alpha-synuclein aggregation: Progress and future outlook.
Chaperone machinery in neurodegeneration: A spotlight on protein misfolding diseases.
Oxidative stress-induced stress granules: a central link to protein aggregation in neurodegenerative diseases.
Amyloidogenic oligomers derived from TDP-43 LCD promote the condensation and phosphorylation of TDP-43.
Neurodegeneration Through the Lens of Bioinformatics Approaches: Computational Mechanisms of Protein Misfolding.
AI-Guided Dual Strategy for Peptide Inhibitor Design Targeting Structural Polymorphs of α-Synuclein Fibrils.
Protein misfolding and its dual role in neurodegeneration and cancer progression.
Proteostasis and pathogenesis: Unraveling the complexity of protein misfolding disorders.
Unravelling γD-crystallin aggregation pathway to understand cataract formation using fluorescence correlation spectroscopy.
Protein misfolding and neurodegeneration: Mechanisms, implications, and therapeutic strategies.
Deubiquitinating Enzymes Ubiquitin-Specific Proteases 7 and 10 Regulate TAU Aggregation.
Neurodegenerative Disease and Autophagy in iPSC models.
Surface wetting is a key determinant of α-synuclein condensate maturation.
Proteostasis network response to environmental chronic stress: linking survival to protein aggregation in a human neuroblastoma cellular model.
Tau4RD fibril polymorphism is imprinted during early aggregation.
Tau seeding in neurons enabled by transient endolysosomal perforations are confined within endolysosomes.
FK506‑binding proteins as emerging bridges linking proteostasis to multi‑system pathogenesis and therapeutic strategies (Review).
Oxidative modification of methionine residue in α-synuclein by dopamine induces cellular vulnerability, oligomerization and secretion of α-synuclein.
Multifaceted Effects of a Multiple Nitric Oxide Photoreleaser and its Photoproducts on Amyloid-β Aggregation.
New Role of Protein Misfolding Corrector in the ER Stress-Inflammation Axis: Possible Therapeutic Indication in Neuronal and Epithelial Tumor Cells.
DEER of Singly Labelled Proteins to Evaluate Supramolecular Packing of Amyloid Fibrils.
Is synuclein aggregation a derived or ancestral trait? Ancestral sequence reconstruction uncovers stepwise evolution of synuclein aggregation.
RNA-Mediated Inhibition Mechanism of Liquid-Liquid Phase Separation and Subsequent Aggregation Revealed by Raman Microscopy.
State-selective small molecule degraders that preferentially remove aggregates and oligomers.
SLP2/PHB Aggregates in ALS Mouse Models and Patients: Implications Beyond CHCHD10-Associated Motor Neuron Disease.
Stress granules and protein aggregates reveal intracellular resource competition.
The Christchurch point mutation in mouse APOE reduces Aβ-induced tau and α-synuclein pathologies.

Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(25)00075-6. [Epub ahead of print]148 379-453

Small molecule inhibitors targeting alpha-synuclein aggregation: Progress and future outlook.

Ishfaq Bashir Hajam, Ishfaq Ahmad Ahanger, Umar Rasool, Tanveer Ali Dar.

  Parkinson's disease (PD), a progressive neurodegenerative disorder, is primarily characterized by the accumulation of alpha-synuclein (α-syn) aggregates in the brain, leading to the neuronal dysfunction and degeneration. As a result, targeting α-syn aggregation is emerging as a promising therapeutic strategy for delaying or stopping disease progression. The present chapter tried to explore the progress made in the development of small molecule inhibitors in preventing or reversing the aggregation of α-syn. Overall, the chapter provides an overview of the mechanisms underlying α-syn misfolding and aggregation, and highlights potential small molecules inhibitors of α-syn aggregation with an update about their clinical trial studies. The chapter also provides current status of clinical trials of these inhibitors. Furthermore, emerging strategies including combination therapies, multi-target approaches, and small molecule-based chaperone therapeutics that might enhance the efficacy of these small molecule inhibitors are discussed. Future directions are also highlighted, emphasizing the emerging potential of small molecule inhibitors in disease-modifying treatments for PD.

Keywords:  Intrinsically disorder protein; Neurodegenerative diseases; Parkinson’s disease; Protein folding; Small molecular probes

DOI:  https://doi.org/10.1016/bs.apcsb.2025.08.017
Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(25)00065-3. [Epub ahead of print]148 455-480

Chaperone machinery in neurodegeneration: A spotlight on protein misfolding diseases.

Abhilasha Sood, Madhumita Dey, Arpit Tyagi, Deepak Kumar Sharma, Arpit Mehrotra.

  Proteins misfolding in neurodegenerative disorders pose a significant challenge to human health and this necessitates a deeper understanding of the fundamental molecular mechanisms. Molecular chaperones are a diverse group of specialized proteins, which are extensively involved in maintaining cellular protein homeostasis and thus preventing aggregation of misfolded proteins. Pathological advancement in several neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD) is characterized by the rampant accretion of misfolded proteins due to chaperonic failure, leading to progressive neuronal dysfunctioning and eventually cell death. Such as in AD, Hsp70 and Hsp90 chaperones are known to interact with β-amyloid and tau proteins, thus preventing their subsequent aggregation with concomitant refolding into native conformations. In PD, chaperones are involved in assisting mitigation of α-Syn misfolding and aggregation, thereby maintaining the normal neuronal functions and their viability. Similarly in HD, chaperones modulate aberrant misfolding of huntingtin protein and its aggregation, thus highlighting prospective therapeutic targets for disease intervention. Nevertheless, further investigating and understanding the explicit roles of chaperones in modulating several protein misfolding diseases holds potential for the development of novel therapeutic approaches. Moreover, targeting such specialized chaperone machinery in restoring protein homeostasis and alleviating subsequent protein aggregation could be considered as a promising approach in managing neurodegenerative disorders.

Keywords:  Alzheimer’s disease; Chaperones; Huntington’s disease; Neurodegeneration; Parkinson’s disease; Protein misfolding diseases

DOI:  https://doi.org/10.1016/bs.apcsb.2025.08.007
Front Neurosci. 2025 ;19 1686571

Oxidative stress-induced stress granules: a central link to protein aggregation in neurodegenerative diseases.

Neelam Younas, Inga Zerr.

  Intracellular aggregation of proteins such as Tau, TDP43, FUS, prion protein, and α-synuclein is a major hallmark of many major neurodegenerative diseases. Aberrant stress granules (SGs) are emerging as key contributors to the nucleation of toxic protein aggregates in these disorders. SGs are dynamic, membrane less cytoplasmic assemblies that form transiently through liquid-liquid phase separation (LLPS) of RNA binding proteins (RBPs) containing low complexity domains, together with stalled mRNAs, to help cells cope with stress. While physiological SGs facilitate cellular resilience to acute stress and undergo rapid disassembly, chronic or excessive stress leads to persistent SGs, driving pathological protein aggregation characteristic of age related neurodegeneration. The inherent reversible aggregation of RBPs crucial for cellular function paradoxically exposes them to misfolding disorders. Notably, recent findings expand this paradigm by demonstrating that Tau itself participates in SG formation, with Tau-SG interactions potentiating Tau aggregation and disease progression in tauopathies. Despite these insights, the precise cellular stressors and posttranslational modifications (PTMs) governing the shift from physiological granules to pathological aggregates remain poorly defined. Emerging evidence highlights oxidative stress as a central upstream mediator of this transition. In this perspective, we synthesize current understanding of how SG dynamics intersect with oxidative stress to potentiate protein aggregation, proposing molecular mechanisms that bridge SG biology and neurodegenerative disease. Elucidating these pathways is essential for the development of targeted therapeutic interventions for disorders such as Alzheimer's disease and related tauopathies.

Keywords:  oxidative stress; pathological aggregation; persistent SGs; stress granules; tauopathies

DOI:  https://doi.org/10.3389/fnins.2025.1686571
Chem Sci. 2025 Nov 14.

Amyloidogenic oligomers derived from TDP-43 LCD promote the condensation and phosphorylation of TDP-43.

Bryan Po-Wen Chen, Chi-Chang Lee, Ruei-Yu He, An-Chi Huang, Jie-Rong Huang, Jerry Chun Chung Chan, Joseph Jen-Tse Huang.

The aberrant aggregation of TAR DNA-binding protein 43 (TDP-43) is a hallmark of amyotrophic lateral sclerosis (ALS). While TDP-43 aggregation can occur via both classical amyloidogenesis and phase separation-mediated mechanisms, the role of amyloidogenic oligomers in modulating TDP-43 condensation remains unclear. Herein, we employ a reverse micelle method to prepare uniform oligomers derived from the low-complexity domain of TDP-43, termed D1core oligomers. These amyloidogenic oligomers are toxic, potently induce phase separation of recombinant TDP-43 C-terminal domains, and promote phosphorylation of cytosolic TDP-43 condensates in cells. Compared to monomeric or fibrillar forms, D1core oligomers uniquely enhance the condensation propensity of wild-type TDP-43 and further potentiate aggregation of the ALS-associated A315T mutant. Live-cell studies using fluorescence recovery after photobleaching reveal that oligomer-induced condensates are modulated by HSP70, which preserves their liquid-like properties. These findings provide new insights into the interplay between TDP-43 oligomers, phase separation, and aggregation, advancing our understanding of ALS-related proteinopathy.

DOI: https://doi.org/10.1039/d5sc05433h
Int J Mol Sci. 2025 Nov 14. pii: 11021. [Epub ahead of print]26(22):

Neurodegeneration Through the Lens of Bioinformatics Approaches: Computational Mechanisms of Protein Misfolding.

Mubashir Hassan, Saba Shahzadi, Ahmed A Moustafa, Andrzej Kloczkowski.

  Protein and peptide aggregation has become a prominent focus in biomedical research due to its critical role in the development of neurodegenerative diseases (NDs) and its relevance to industrial applications. Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS) are closely associated with abnormal aggregation processes, highlighting the need for a deeper understanding of their molecular mechanisms. In recent years, a wide range of computational methods, bioinformatics tools, and curated databases have been developed to predict and analyze sequences and structures that are prone to aggregation. These in silico approaches offer valuable insights into the underlying principles of aggregation and contribute to the identification of potential therapeutic targets. This review provides a concise overview of the current bioinformatics resources and computational techniques available for studying protein and peptide aggregation, intending to guide future research efforts in the field of neurodegenerative disease modeling and drug discovery.

Keywords:  bioinformatics; computational methods; databases; neurodegenerative diseases; protein aggregation

DOI:  https://doi.org/10.3390/ijms262211021
bioRxiv. 2025 Oct 13. pii: 2025.10.10.681708. [Epub ahead of print]

AI-Guided Dual Strategy for Peptide Inhibitor Design Targeting Structural Polymorphs of α-Synuclein Fibrils.

Jinfang Duan, Haoyu Zhang, Chuanqi Sun.

One of the most important events in the pathogenesis of Parkinson's disease and related disorders is the formation of abnormal fibrils via the aggregation of α-synuclein (α-syn) with β-sheet-rich organization. The use of Cryo-EM has uncovered different polymorphs of the fibrils, each having unique structural interfaces, which has made the design of inhibitors even more challenging. Here, a structure-guided framework incorporating AI-assisted peptide generation was set up with the objective of targeting the conserved β-sheet motifs that are present in various forms of α-syn fibrils. The ProteinMPNN, then, AlphaFold-Multimer, and PepMLM were employed to create short peptides that would interfere with the growth of the fibrils. The two selected candidates, T1 and S1, showed a significant inhibition of α-syn fibrillation, as measured by a decrease in the ThT fluorescence and the generation of either amorphous or fragmented aggregates. The inhibitory potency of the peptides was in line with the predicted interface energies. This research work illustrates that the integration of cryo-EM structural knowledge with the computational design method leads to the quick discovery of the wide-spectrum peptide inhibitors, which is a good strategy for the precision treatment of neurodegenerative diseases.

DOI: https://doi.org/10.1101/2025.10.10.681708
Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(25)00088-4. [Epub ahead of print]148 355-377

Protein misfolding and its dual role in neurodegeneration and cancer progression.

Rajeshwer Singh Jamwal, Bhawani Sharma, Minerva, Agamya Gupta, Swati Misri, Raju Shankaryan, Ruchi Shah, Rakesh Kumar.

  Protein misfolding is a fundamental biological process with profound implications for human health and disease. Typically, proteins assume precise three-dimensional structures to perform their functions, a process safeguarded by the proteostasis network, which comprises molecular chaperones, the ubiquitin-proteasome system (UPS), and autophagy. However, genetic mutations, oxidative stress, and environmental insults can disrupt folding, leading to the accumulation of non-functional or toxic conformations. In neurodegenerative diseases such as Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral Sclerosis (ALS), chronic misfolding results in toxic protein aggregates like amyloid-β, tau, and α-synuclein. These disrupt synaptic function, induce oxidative and nitrosative stress, and trigger apoptosis, ultimately leading to progressive neuronal loss. Dysregulation of the unfolded protein response (UPR) and weakened proteostasis with aging exacerbate disease pathology. In contrast, cancer cells utilize protein misfolding to enhance their survival and progression. Misfolded oncoproteins, such as mutant p53, not only evade degradation but also acquire oncogenic properties. Tumor cells hijack the UPR and chaperone networks, upregulate heat shock proteins, and manipulate oxidative stress responses to withstand hypoxia, nutrient deprivation, and rapid proliferation. Cancer stem cells (CSCs) further adapt to proteotoxic stress, contributing to tumor heterogeneity, therapy resistance, and immune evasion. The dual role of protein misfolding, driving degeneration in neurons while supporting proliferation in tumors, underscores its centrality in disease biology. Future research should focus on identifying early biomarkers of proteostasis imbalance and exploiting shared molecular pathways for the development of novel therapeutic interventions.

Keywords:  Cancer progression; Molecular chaperones; Neurodegeneration; Protein misfolding; Proteostasis; Ubiquitin–proteasome system (UPS); Unfolded protein response (UPR)

DOI:  https://doi.org/10.1016/bs.apcsb.2025.10.001
Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(25)00071-9. [Epub ahead of print]148 299-353

Proteostasis and pathogenesis: Unraveling the complexity of protein misfolding disorders.

Tripti Nair, Ditsa Sarkar, Sumit Murmu, Rahul Singh Rawat, Biplab Singha.

  Within the cellular milieu, protein molecules must fold into precise three-dimensional structures to attain functionality. Protein chains can assume many misfolded states during this critical process. Such errant configurations are unstable and can aggregate into toxic misfolded conformations. In protein misfolding disorders, polypeptides are folded in an aberrant manner, resulting in non-functional and often pathogenic states. Protein folding is fundamental to biological function, and disruption of the process can result in toxic aggregates, such as oligomers and amyloid fibrils, which are implicated in a variety of diseases, particularly neurodegenerative diseases such as Alzheimer's and Parkinson's. Here, we examine the delicate interplay of forces that determine the native conformation of proteins and how perturbations in this balance lead to disease. A critical aspect of our discussion is the cell's proteostasis network, a complex network of molecular chaperones and regulators responsible for regulating protein folding and maintaining the health of the cell. In this chapter, we discuss how intrinsic protein properties, post-translational modifications, and extrinsic environmental factors can destabilize proteins, thereby resulting in their misfolding. Several pathogenic mechanisms will be elucidated, including the progression from a misfolded protein to the development of disease phenotypes. Next, the chapter will present an overview of the current therapeutic approaches to mitigate the diseases caused by protein misfolding. Using the latest findings in clinical and experimental research, we will evaluate the therapeutic landscape, ranging from small-molecule inhibitors to chaperone-based therapies.

Keywords:  Molecular chaperones; Neurodegenerative diseases; Oxidative stress; Post-translational modifications; Protein aggregation; Protein misfolding; Proteostasis; Ubiquitin-proteasome system

DOI:  https://doi.org/10.1016/bs.apcsb.2025.08.013
Mol Vis. 2025 ;31 231-243

Unravelling γD-crystallin aggregation pathway to understand cataract formation using fluorescence correlation spectroscopy.

Mangesh Bawankar, Bhaswati Sengupta, Sujata Malik, Pratik Sen, Ashwani K Thakur.

Purpose: To characterize the aggregation behavior of the γD-crystallin protein in an acidic environment with a focus on the formation of intermediate species. The research employs fluorescence correlation spectroscopy to unravel the intricate molecular events leading to aggregation, contributing to a comprehensive understanding of cataract formation.
Methods: The kinetics of γD-crystallin protein aggregation were studied with a reversed-phase high-performance liquid chromatography sedimentation assay, a ThT binding assay, and light scattering. We used fluorescence correlation spectroscopy (FCS) to recognize intermediate aggregate species and characterized them with Fourier transform infrared spectroscopy (FTIR). Further, the morphologic characterization of aggregates was done by transmission electron microscopy (TEM), and their hydrophobic characteristics were analyzed using the 8-anilino-1-naphthalenesulfonic acid binding assay.
Results: A negligible lag phase was observed in the aggregation kinetic experiments of the γD-crystallin protein. Pentamer, 25-mer, and higher oligomer intermediates were formed on the aggregation pathway. Conformation studies by FCS and FTIR have shown that oligomers are rich in cross-β sheet and random coil structure; however, they constitute more α-helix and less cross-β sheet structure than fibrils. TEM analysis revealed the approximate size of oligomers (diameter ~10 nm), protofibrils (~15 nm), and fibrils (~15 to ~35 nm).
Conclusions: In this study, we reported the presence of various intermediate aggregate species formed on the aggregation pathway of γD-crystallin protein at low pH. This will open new areas of research in understanding the detailed aggregation mechanism and aggregation hotspot within unfolded γD-crystallin monomers. The insights gained will also pave the way for future research in the realm of amyloid formation in cataract.
Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(25)00070-7. [Epub ahead of print]148 135-177

Protein misfolding and neurodegeneration: Mechanisms, implications, and therapeutic strategies.

Asma Shah, Tharini Karthikeyan, Sheema Hashem, Rakesh Kumar, Ajaz A Bhat, Muzafar A Macha.

  Protein misfolding and aggregation play a pivotal role in the development of neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's disease, and other related disorders. Proper protein folding is essential for cellular function, but due to the complexity of the folding process and external factors like genetic mutations, oxidative stress, and aging, misfolding is inevitable. These misfolded proteins often aggregate into toxic forms that disrupt cellular processes, leading to neuronal damage and cognitive decline. This chapter provides a comprehensive overview of molecular mechanisms behind protein misfolding, highlighting how these abnormal structures contribute to neurodegeneration. It also explores the role of the proteostasis network and its therapeutic potential in alleviating these processes. Focusing on multitarget therapeutic strategies, the chapter offers insights into promising approaches for addressing the root causes of neurodegenerative diseases while identifying key research gaps that could shape future treatment developments. By blending current knowledge with emerging therapeutic directions, this chapter provides a comprehensive and engaging perspective on combating the challenges of protein misfolding in neurodegeneration.

Keywords:  Amyloid fibrils; Molecular chaperones; Neurodegenerative disorders; Neuronal toxicity; Protein misfolding; Therapeutic targets; Unfolded protein response (UPR)

DOI:  https://doi.org/10.1016/bs.apcsb.2025.08.012
Int J Mol Sci. 2025 Nov 15. pii: 11062. [Epub ahead of print]26(22):

Deubiquitinating Enzymes Ubiquitin-Specific Proteases 7 and 10 Regulate TAU Aggregation.

Christiane Volbracht, Karina Fog.

  Accumulation of the microtubule-associated protein TAU into inclusions is a hallmark of tauopathies including Alzheimer's disease (AD), potentially driven by impaired protein degradation and dysregulated ubiquitination. To explore the role of deubiquitinating enzymes (DUBs), we performed siRNA knockdown screens targeting 93 murine DUBs in rTg4510 cortical cultures. Knockdown and pharmacological inhibition of the ubiquitin-specific proteases 7 (Usp7) and 10 (Usp10) significantly reduced seeded TAU aggregation without affecting soluble TAU levels. These effects were observed in both cortical and organotypic hippocampal slice cultures from rTg4510 mice, as well as in wildtype neurons seeded with AD-derived pathological TAU. Inhibition of Usp7 and Usp10 was associated with increased polyubiquitination of residual TAU inclusions in rTg4510 cortical cultures. These findings suggest that Usp7 and Usp10 contribute to pathological TAU accumulation by modulating ubiquitin-dependent degradation pathways. Targeting USP7 and USP10 may offer a novel therapeutic strategy for AD and related tauopathies.

Keywords:  Alzheimer’s disease; USP10; USP7; rTg4510; tauopathy; ubiquitin

DOI:  https://doi.org/10.3390/ijms262211062
Neurosci Res. 2025 Nov 26. pii: S0168-0102(25)00174-9. [Epub ahead of print] 104991

Neurodegenerative Disease and Autophagy in iPSC models.

Sodbileg Odonchimed, Keiko Imamura, Haruhisa Inoue.

  Neurodegenerative diseases are characterized by the gradual deterioration of specific neuronal populations, ultimately resulting in motor, cognitive, or behavioral impairments. Despite the worldwide increase in disease incidence, effective therapies remain unavailable. A common pathological hallmark of neurodegenerative diseases is the accumulation of misfolded protein aggregates, which impair normal cellular function. Accordingly, numerous studies and therapeutic strategies have focused on targeting these toxic aggregates and protein quality control via autophagy, a vital cellular recycling mechanism. Autophagy dysregulation has been implicated in the pathogenesis of several neurodegenerative diseases. Induced pluripotent stem cell (iPSC) technology has emerged as a powerful platform for modeling neurodegenerative diseases, and iPSC-derived models provide human-relevant systems for studying autophagic dysfunction in vitro. In this review, we discuss the key findings of recent studies investigating autophagy in iPSC-based models of neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and other diseases.

Keywords:  autophagy; disease model; iPSCs; neurodegenerative disease

DOI:  https://doi.org/10.1016/j.neures.2025.104991
Commun Chem. 2025 Nov 27. 8(1): 379

Surface wetting is a key determinant of α-synuclein condensate maturation.

Rebecca J Thrush, Devkee M Vadukul, Siân C Allerton, Marko Storch, Francesco A Aprile.

α-Synuclein condensates can mature into amyloid fibrils, demonstrating a link between phase separation and amyloid aggregation. However, the mechanisms driving this maturation are not fully understood, particularly in the context of pathological post-translational modifications that modulate α-synuclein amyloid aggregation. Although often studied in isolation, condensates appear to interact with surfaces in vitro and in the cell. Notably, the N-terminus of α-synuclein is implicated in membrane binding and may influence condensate-surface interactions. Here, we developed a microscopy-based protocol to investigate how N-terminal truncation affects α-synuclein condensate formation, surface wetting, and maturation. We found that N-terminal truncation enhances condensate wettability and accelerates maturation. Conversely, perturbing condensate-surface interactions reduces condensate wettability and delays maturation. These results suggest that enhanced wettability promotes condensate maturation, likely by increasing condensate surface-to-volume ratios. Our findings reveal distinct mechanistic roles for the N-terminus of α-synuclein and highlight condensate wettability and interfacial dynamics as key modulators of aggregate formation.

DOI: https://doi.org/10.1038/s42004-025-01764-z
Cell Mol Life Sci. 2025 Nov 27. 82(1): 430

Proteostasis network response to environmental chronic stress: linking survival to protein aggregation in a human neuroblastoma cellular model.

Emiliano Montalesi, Daniela Caissutti, Camilla Moliterni, Antonella Ferrante, Rita Pepponi, Tina Garofalo, Maurizio Sorice, Roberta Misasi, Niccolò Candelise.

  Proteins tend to misfold upon stressful events that alter their homeostasis, potentially leading to protein aggregation. A tight regulation of synthesis, folding and degradation, defined as proteostasis network (PN), is required to ensure the functionality of the cell. PN is of utmost importance in post-mitotic cells such as neurons, where protein quality must be preserved for their entire lifetime. Most neurodegenerative disorders are associated with dysregulation of this network. Here, we describe the alteration in key components of the PN during chronic stress and link them with the increase in the amyloid burden and with the aggregation of the protein TDP-43, a major player in Amyotrophic Lateral Sclerosis and other neurodegenerative diseases. Neuroblastoma SH-SY5Y cells were treated with a panel of environmental stressors and analyzed after 24 h and 72 h. Treatments resulted in altered PN functionality, including proteasome impairment, halted protein synthesis, engulfed bulk and selective autophagy, in the absence of overt cell death. Thioflavin staining showed increased amyloid burden throughout treatments, associated with phosphorylated TDP-43 (pTDP-43). Biochemical analyses further revealed the cleavage and increased insolubility of pTDP-43. Our results suggest that TDP-43 is a central player during the integrated stress response to chr onic insults and that increased amyloid burden may reflect the global wellfare of a cellular system, pointing toward the alteration of the PN as the main drive for the onset of sporadic neurodegenerative disorders.

Keywords:  Cell fate; Cellular homeostasis; Prion-like; Protein misfolding; Protein quality control; Protein solubility

DOI:  https://doi.org/10.1007/s00018-025-05884-6
bioRxiv. 2025 Oct 14. pii: 2025.10.12.681486. [Epub ahead of print]

Tau4RD fibril polymorphism is imprinted during early aggregation.

Ellie I James, Mason Saunders, Kelly K Lee, Miklos Guttman, Abhinav Nath.

Microtubule-associated protein tau forms characteristic fibrillar species in many neurodegenerative diseases. Neurofibrillary tangles, tau deposits observed in Alzheimer's disease (AD), contain a mixture of amyloid-type polymorphic fibrils called paired helical filaments (PHFs) and straight filaments. The formation of heterogenous fibril populations is observed in other diseases and when tau aggregation is induced in vitro with polyanionic species. This suggests that tau's structural transition from a conformational ensemble to various amyloid morphologies is a controlled and, therefore, controllable process. Despite many years of work toward describing aggregation intermediates that could address open questions such as whether fibril polymorphism is imprinted at the start of aggregation or arises due to conformational conversions, our understanding of amyloid structure remains predominantly based on observations of mature fibrils. It is unclear whether these processes are mutually exclusive and to what extent we can bias intermediate conformations toward less toxic states. Here to address the challenge of studying aggregation intermediates and tau's structural conversion, we apply pulsed hydrogen-deuterium exchange with mass spectrometry (pulsed HDX-MS), which revealed differences in the subpopulations formed by tau4RD (a truncated tau construct) within seconds of initiating aggregation with polyphosphate and within hours of heparin-induction. This work begins to address the gap in knowledge regarding whether amyloid polymorphism is directly imprinted during nucleation or results from structural rearrangement during later stages of aggregation.

DOI: https://doi.org/10.1101/2025.10.12.681486
bioRxiv. 2025 Nov 03. pii: 2025.11.02.686178. [Epub ahead of print]

Tau seeding in neurons enabled by transient endolysosomal perforations are confined within endolysosomes.

Anwesha Sanyal, Gustavo Scanavachi, Elliott Somerville, Beren Aylan, Jose Inacio Costa-Filho, Forest Brooks, John R Dickson, Bradley T Hyman, Tom Kirchhausen.

Pathogenic tau assemblies propagate by templated seeding. For endocytosed fibrils to initiate aggregation of endogenous tau, a breach must occur in the limiting membrane of an endosome or lysosome. To study the route by which internalized tau seeds access cytosolic monomers and to identify the site of aggregate growth, we imaged live human iPSC-derived neurons (iNs) expressing tau P301L-eGFP after exposure to recombinant tau pre-formed fibrils (PFFs) or Alzheimer's disease (AD) brain-derived oligomers or fibrils. We detected seeded tau P301L- eGFP aggregation within late endosomes/lysosomes of iNs but not in undifferentiated iPSCs. Colocalization with a Dextran pH biosensor showed that the aggregates remained within the lumen of an intact, low-pH compartment. Reporters of endolysosomal injury and repair (endolysosomal recruitment cytosolic galectin-3 and the ESCRT-III component IST1) did not change during seeding. Volume focused-ion-beam scanning electron microscopy showed fibrillar material exclusively inside membrane-bounded endolysosomes, with no membrane discontinuities in the fibril-containing compartments and with no evidence of cytosolic aggregates. Because tau and α-synuclein can cross-seed, we adapted a HaloTag pulse-chase assay to test for the persistence of trans-membrane access. AD fiber-containing endolysosomes progressively recruited cytosolic α-synuclein-Halo over days, with heterogeneous incorporation histories consistent with recurrent, self-limited access events rather than persistent rupture or terminal sealing. Pharmacologic inhibition of the endolysosomal lipid kinase PIKfyve with apilimod suppressed seeded tau aggregation and prevented neuronal toxicity. These data indicate that templated conversion proceeds within acidic, membrane-intact endolysosomes; tau seeding in neurons is enabled by transient, self-limited endolysosomal perforations yet remains confined to the endolysosomal lumen, and it requires PIKfyve- dependent PI(3,5)P₂.

DOI: https://doi.org/10.1101/2025.11.02.686178
Int J Mol Med. 2026 Jan;pii: 30. [Epub ahead of print]57(1):

FK506‑binding proteins as emerging bridges linking proteostasis to multi‑system pathogenesis and therapeutic strategies (Review).

Zhi Li, Xiaolei Liu, Hesong Zeng.

  Protein homeostasis, or proteostasis, refers to the integrated quality control systems that regulate protein synthesis, folding, post‑translational modification, trafficking and degradation to maintain proteome stability and function. Disruption of these processes, including abnormal synthesis, misfolding or impaired degradation, results in proteostasis collapse and underlies the pathogenesis of cancer, neurodegeneration, cardiovascular disease and metabolic syndromes. Recent studies have highlighted FK506‑binding proteins (FKBPs), a family of immunophilins defined by a conserved peptidyl‑prolyl cis‑trans isomerase domain, as pivotal modulators of proteostasis. By modulating protein folding, stabilizing complexes, regulating endoplasmic reticulum stress and directing selective degradation, FKBPs establish direct links between proteostasis regulation and disease progression. This review presents the first comprehensive synthesis of FKBP‑mediated control of proteostasis across diverse clinical contexts. It analyzed how their structural features confer regulatory potential and elucidate their roles in proteome remodeling in cancer, pathogenic protein aggregation in neurodegenerative disorders, ion channel stabilization in cardiovascular dysfunction and kinase phosphorylation in metabolic regulation. By integrating these diverse actions within a unified proteostasis framework, FKBPs are proposed as versatile regulators and promising therapeutic targets, providing new perspectives on the proteostasis‑disease axis and opportunities for precision intervention across multiple organ systems.

Keywords:  FK506‑binding proteins; cancer; cardiovascular diseases; metabolic dysregulation; neurodegenerative diseases; proteostasis

DOI:  https://doi.org/10.3892/ijmm.2025.5701
J Clin Biochem Nutr. 2025 Nov 01. 77(3): 216-222

Oxidative modification of methionine residue in α-synuclein by dopamine induces cellular vulnerability, oligomerization and secretion of α-synuclein.

Yugo Kato, Masahiro Kanatani, Tadashi Adachi, Hidetoshi Nagamine, Yosuke Horikoshi, Kazuhiro Nakaso.

  Parkinson's disease (PD) is a neurodegenerative disorder characterized by the selective loss of dopamine (DA) neurons and presence of Lewy bodies, with prion-like propagation of α-synuclein (α-syn) also attracting attention recently. However, the specific causes for PD-related pathogenesis, including cell vulnerability and α-syn propagation, occurring only in selective neurons remain unclear. Therefore, we aimed to investigate the interactions between DA and α-syn protein to clarify its effects on α-syn degradation, secretion, and toxicity. We generated PC12 cells expressing human α-syn and M127A mutant in a tetracycline-inducible manner. In these cells, intracellular α-syn levels were controlled via autophagic/lysosomal degradation and secretion to extracellular space. Notably, M127A mutation decreased the intracellular degradation and secretion of α-syn. Using the generated cells, we investigated the association between cell viability and oxidized methionine [Met(O)] in α-syn. We also investigated the effects of Met(O) on α-syn toxicity and stability upon DA induction. Wildtype α-syn overexpression decreased the cell viability, and inhibition of methionine sulfoxide reductase, a methionine sulfoxide-reducing enzyme, further amplified this effect, suggesting that α-syn cytotoxicity is associated with methionine oxidation. Notably, vulnerabilities of M127A mutant cells were lower than those of wildtype α-syn-expressing cells. Overall, our results suggest M127 as the major target for oxidative modification by DA and that this modification is associated with both cell vulnerability and α-syn intracellular stability and secretion in PD pathogenesis.

Keywords:  Parkinson’s disease; dopamine; methionine sulfoxide reductase; oxidative modification; α-synuclein

DOI:  https://doi.org/10.3164/jcbn.25-74
Chembiochem. 2025 Nov 24. e202500667

Multifaceted Effects of a Multiple Nitric Oxide Photoreleaser and its Photoproducts on Amyloid-β Aggregation.

Francesca Laneri, Cristina Parisi, Salvatore Sortino.

  Aberrant aggregation of β-amyloid (Aβ) peptides into insoluble fibrils is recognized as one of the hallmarks of Alzheimer's disease (AD). Among the post-translational modifications influencing Aβ behavior, nitration and nitrosation by nitric oxide (NO) derivatives play a key role, though their impact on aggregation and toxicity remains unclear. This contribution explores the effects on Aβ aggregation induced by an NO photodonor (NOPD) releasing two NO molecules via a stepwise mechanism under the control of visible blue light. Significant reduction of protein aggregation is observed when a considerable amount NO (≈120 µM) is photoreleased during the early stages of the protein aggregation. In contrast, long-term release of a similar NO concentration is ineffective. On the other hand, proaggregative effect is induced by the NOPD kept in the dark. The stable photoproducts formed after the release of the first and the second molecule of NO also show a protein aggregation inhibitory effect both individually and in combination. Dynamic simulation studies are also reported to shed light on the binding of NOPD and its photoproducts with key Aβ1-40 residues.

Keywords:  Alzheimer; amyloid; light; nitric oxide; organofluoride

DOI:  https://doi.org/10.1002/cbic.202500667
Int J Mol Sci. 2025 Nov 08. pii: 10846. [Epub ahead of print]26(22):

New Role of Protein Misfolding Corrector in the ER Stress-Inflammation Axis: Possible Therapeutic Indication in Neuronal and Epithelial Tumor Cells.

Michela Pecoraro, Adele Serra, Maria Julia Lamberti, Maria Pascale, Silvia Franceschelli.

  Protein misfolding diseases are characterized by structurally abnormal proteins that lose their functionality, resulting in cellular and tissue dysfunction. Neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Huntington's disease, share a common etiopathogenesis characterize by the accumulation of misfolded proteins. These proteins autonomously aggregate within neuronal cells, triggering inflammation and cell death. The accumulation of misfolded proteins triggers endoplasmic reticulum (ER) stress, leading to alter Ca2+ homeostasis. This prolonged stress condition induces the cleavage of procaspase 4 which is resident in ER and activates NF-kB pathway activation, leading to inflammatory responses and cell death. In this study, the efficacy of the drug Vx-445 (Elexacaftor), used in the pharmacological treatment of cystic fibrosis, was assessed in human adenocarcinomic basal alveolar epithelial (A549) and neuronal (SH-SY5Y) cell lines, where ER stress was induced by Thapsigargin. The aim was to assess whether the corrector was able to reduce ER stress by restoring cellular homeostasis and, probably, the proper folding of misfolded proteins and reducing the inflammatory response triggered by these events. Therefore, protein levels of IkBα, p-STAT 3 and COXII were analyzed by flow cytofluorimetry, while Ca2+ content was measured by spectrofluorimetry. The results obtained suggest a significant effect of Vx-445 in restoring cellular homeostasis, leading to reduced expression of inflammation-related proteins, such as IL-6, tested by ELISA. Although preliminary, these results encourage further studies to explore the potential repurpose of Vx-445 as a therapeutic candidate for conditions involving ER stress and chronic inflammatory diseases associated with protein misfolding, beyond its current use in cystic fibrosis.

Keywords:  ER stress; corrector; inflammation; misfolding protein; neurodegenerative disease

DOI:  https://doi.org/10.3390/ijms262210846
bioRxiv. 2025 Nov 12. pii: 2025.11.10.687719. [Epub ahead of print]

DEER of Singly Labelled Proteins to Evaluate Supramolecular Packing of Amyloid Fibrils.

Karen Tsay, Asif Equbal, Yuanxin Li, Tiffany Tsui, Songi Han, Yann Fichou.

The formation of protein amyloid fibrils in the brain is a hallmark of various neurodegenerative diseases, including Alzheimer diseases and Parkinson diseases. Amyloid fibrils are highly ordered aggregates in which proteins folded in two-dimensional layers stack along one axis to form elongated linear assemblies. The specific conformations adopted by the proteins within each layer of the amyloid correlates with the pathology. Furthermore, their spreading and templating competency relies on strict in register packing of the folded proteins along the fibril growing axis. There is a need for tools to characterize not only the protein fold across the fibril cross section but also the spatial ordering of the proteins stacked along the amyloid fibril axis. We present an approach based on double electron electron resonance spectroscopy (DEER) using singly labelled tau protein assembled in amyloid fibrils that can deliver an apparent dimensionality of the supramolecular organization of tau fibrils. The parameters of the DEER background function can be used to assess the amyloid core location and packing order, and track time-resolved formation of aggregation intermediates. Showcasing the method on tau, we demonstrate that heparin-induced tau fibrils are mispacked while seeded aggregation can template amyloid fibrils with a higher packing order. This study benchmarks a new method that will provide critical structural insights into amyloid assemblies.
Abstract Figure:

DOI: https://doi.org/10.1101/2025.11.10.687719
bioRxiv. 2025 Sep 27. pii: 2025.09.27.678990. [Epub ahead of print]

Is synuclein aggregation a derived or ancestral trait? Ancestral sequence reconstruction uncovers stepwise evolution of synuclein aggregation.

Andrew Sam, Seungwoo Lee, Jordan Elliott, Emma Larson, Abdullah Naiyer, Jonathan K Williams, Jean Baum.

Protein aggregation drives many neurodegenerative diseases, including Parkinson's disease, where misfolded α-synuclein (αSyn) forms fibrillar assemblies that accumulate as Lewy bodies. Although αSyn aggregation has been extensively characterized, its evolutionary origins and sequence determinants remain unresolved. Here, we use ancestral sequence reconstruction (ASR) to trace the emergence of fibril-forming ability in the synuclein family. We inferred synuclein phylogeny and experimentally resurrected common ancestors, including ROOT synuclein, the last common ancestor of all synucleins, and key intermediates along the αSyn lineage. Strikingly, ROOT synuclein is non-aggregating, demonstrating that fibril formation is an evolved, rather than ancestral property. Aggregation first emerges at the ancestral αβ node, is retained in αSyn, and suppressed in β-synuclein. Biophysical analyses including mass spectrometry and NMR reveal that aggregation aligns with greater complexity and heterogeneity in the monomer conformational ensemble, suggesting that evolutionary sequence changes progressively remodel monomer landscapes to favor fibril formation. Complementing these insights, comparative sequence analysis reveals that the transition from ROOT to α-WT is marked by the stepwise acquisition of residues critical for stabilizing the fibril core. Early mutations stabilized the β-arch core, enabling the onset of fibril formation, followed by substitutions that reinforce protofilament-protofilament interactions. Together, ASR defines an evolutionary framework for synuclein aggregation linking progressive sequence evolution and conformational complexity to the molecular origins of αSyn fibril formation.

DOI: https://doi.org/10.1101/2025.09.27.678990
JACS Au. 2025 Nov 24. 5(11): 5749-5757

RNA-Mediated Inhibition Mechanism of Liquid-Liquid Phase Separation and Subsequent Aggregation Revealed by Raman Microscopy.

Taisei Ogura, Uchu Matsuura, Masato Machida, Kaichi Nagai, Shinji Kajimoto, Shinya Tahara, Takakazu Nakabayashi.

  Liquid-liquid phase separation (LLPS) is a phenomenon where homogeneous solutions of biomacromolecules separate into two liquid phases and generate liquid droplets enriched in specific biomolecules. LLPS of neurodegeneration-related proteins, including fused in sarcoma (FUS), promotes their aggregation, causing fatal diseases such as amyotrophic lateral sclerosis (ALS). Recent studies showed that RNAs regulate LLPS of these proteins and inhibit their aggregation, which may play an important role in preventing the disease onset; however, the underlying molecular mechanisms remain elusive. It is also unknown whether endogenous RNAs regulate LLPS and subsequent aggregation in cells. In this study, we investigated features of RNAs that enable their entrance into FUS droplets and inhibition of FUS aggregation via droplets and clarified the underlying mechanisms using Raman microscopy. We found that RNA length is one of the primary factors governing both the aggregation-inhibition effect and the localization of RNAs in the droplets in buffer solutions. Short (<50-nt) RNAs were concentrated inside the droplets and inhibited the aggregation. Our quantification method using Raman microscopy revealed that the short RNAs are enriched in FUS droplets by binding to FUS proteins through electrostatic interactions. On the other hand, long (>1000-nt) RNAs were not concentrated and dissolved the droplets. Raman imaging of living cells revealed that intracellular FUS droplets are enriched with endogenous RNAs at levels comparable to in vitro droplets and exhibit high fluidity, confirming that endogenous RNAs play a crucial role in suppressing droplet-to-aggregate transition of FUS in cells. These findings indicate that short RNAs stabilize FUS droplets through heterotypic RNA-FUS interactions that compete with homotypic FUS-FUS direct contacts responsible for aggregation, whereas binding of long RNAs enhances FUS solubility and promotes droplet dissolution. Our study highlights the protective role of RNAs against pathogenic aggregation of neurodegeneration-related proteins via droplets.

Keywords:  Liquid−liquid phase separation; Neurodegenerative diseases; Protein aggregation; RNA; Raman microscopy

DOI:  https://doi.org/10.1021/jacsau.5c01234
Nat Commun. 2025 Nov 25. 16(1): 10486

State-selective small molecule degraders that preferentially remove aggregates and oligomers.

Jakub Luptak, Dean Clift, Aamir Mukadam, Jonathan Benn, Tyler Rhinesmith, Stephen H McLaughlin, Amy C Dodds, Jerson E Lapetaje, Matylda Sczaniecka-Clift, David J France, William A McEwan, Leo C James.

TRIM21 is a unique E3 ligase that uses a clustering-based activation mechanism to degrade complex multimeric substrates. This activity underpins the targeted protein degradation technology Trim-Away and genetically encoded degraders that selectively target aggregated tau protein and prevent tauopathy. Here we describe small molecules that mimic TRIM21's natural epitope and function as either effective inhibitors or potent and selective degraders called TRIMTACs. TRIMTACs mediate degradation as rapidly as PROTACs but can also selectively degrade specific protein pools depending on assembly state. We demonstrate the utility of this state-specific degradation by selectively removing the pro-inflammatory signalling protein Myd88 when assembled into the Myddosome and the cell-death protein RIPK3 when polymerised into the Necrosome. We further show that TRIMTACs can inhibit seeded tau aggregation under conditions where a PROTAC is ineffective. These results highlight that TRIM21's clustering-based activation can be exploited by small molecule degraders to carry out state-selective degradation of therapeutic targets.

DOI: https://doi.org/10.1038/s41467-025-65454-z
Int J Mol Sci. 2025 Nov 08. pii: 10852. [Epub ahead of print]26(22):

SLP2/PHB Aggregates in ALS Mouse Models and Patients: Implications Beyond CHCHD10-Associated Motor Neuron Disease.

Emmanuelle C Genin, Françoise Lespinasse, Alessandra Mauri-Crouzet, Luc Dupuis, Véronique Paquis-Flucklinger.

  Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motor neuron (MN) degeneration, frequently overlapping with frontotemporal dementia (FTD). Protein aggregation is a hallmark of these disorders, yet the role of aggregates in ALS pathogenesis remains unclear. Previously, stomatin-like protein 2 (SLP2) and prohibitin (PHB) aggregates were identified in a model of CHCHD10-related ALS (Chchd10S59L/+ mice). This study raises the question of the presence and possible involvement of these aggregates in ALS beyond CHCHD10-associated motor neuron disease (MND). Using immunohistofluorescence, we analyzed SLP2/PHB expression in the spinal MNs and hippocampus of two ALS mouse models: FusΔNLS and Sod1G86R. Additionally, post-mortem spinal cord tissues from 27 ALS and ALS-FTD patients were analyzed. SLP2/PHB aggregates were identified in spinal MNs and the hippocampus of FusΔNLS mice but not in Sod1G86R mice. In ALS patients, SLP2/PHB aggregation was observed in four cases, including two with C9ORF72 mutations. Interestingly, aggregates were absent in SOD1-associated ALS patients. These findings suggest that SLP2/PHB aggregation is not specific to CHCHD10 variants but may contribute to the pathogenesis of ALS from different origins. The age-related accumulation of these aggregates highlights their potential role in disease progression and as therapeutic targets. Future studies should investigate their mechanistic contributions across different ALS subtypes.

Keywords:  Amyotrophic Lateral Sclerosis; CHCHD10; SLP2/PHB aggregates; motor neuron disease

DOI:  https://doi.org/10.3390/ijms262210852
bioRxiv. 2025 Nov 10. pii: 2025.11.08.687377. [Epub ahead of print]

Stress granules and protein aggregates reveal intracellular resource competition.

Hannah E Buchholz, Sean A Martin, Jane E Dorweiler, Derek C Prosser, Emily M Sontag, Anita L Manogaran.

Stress granules are biomolecular condensates that form in response to environmental stress and disassemble once normal conditions are restored. However, when disassembly fails, stress granules can persist and solidify. While stress granule solidification has been well documented, the cellular mechanisms underlying the transition from reversible to persistent stress granules remain unclear. Persistent stress granules can seed the formation of pathological aggregates, such as TDP-43 in amyotrophic lateral sclerosis 1, 2 . Although amyloid and tau aggregates are hallmarks of Alzheimer's disease, a subset of patients also develop TDP-43 deposits, suggesting a possible role for stress granule solidification in Alzheimer's disease progression 3-5 . Despite theoretical models explaining why persistence and ensuing solidification occurs, strong in vivo evidence is lacking 6 . Here we show that competition for limited chaperone resources drive stress granule persistence. In the presence of TDP-43 aggregates or yeast amyloid proteins called prions, stress granule disassembly is slowed or halted disassembly. Using yeast prions as a model, we show that the addition of chaperones, specifically the AAA+ ATPase molecular chaperone, Hsp104, resulted in resumption of stress granule disassembly. Our results demonstrate that the competition for shared resources, such as molecular chaperones, can limit stress granule disassembly. We suspect that the presence of pathological aggregates results in resource competition within the aging brain, contributing to the persistence of stress granules and their subsequent solidification and aggregation.

DOI: https://doi.org/10.1101/2025.11.08.687377
bioRxiv. 2025 Nov 07. pii: 2025.11.05.686857. [Epub ahead of print]

The Christchurch point mutation in mouse APOE reduces Aβ-induced tau and α-synuclein pathologies.

Carlos M Soto-Faguás, Abigail O'Niel, Paul A Mueller, Paula Sanchez-Molina, Randy L Woltjer, Jacob Raber, Vivek K Unni.

Apolipoprotein E ( APOE ) genotype is well known to influence both amyloid-β (Aβ) and tau pathologies and risk for Alzheimer's disease (AD), but it also affects α-synuclein (α-syn) levels, Lewy pathology and risk of dementia in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The APOE-R136S (Christchurch, CC) point mutation has been shown to protect against AD pathology and dementia, however, the molecular mechanisms underlying this protection and its effects on α-syn pathology are not well understood. Using CRISPR/Cas9 technology, we created a CC arginine-to-serine point mutation at the conserved location in mouse APOE (R128S) to understand its effects on Aβ, tau and α-syn pathologies. We crossed these APOE CC mice to 5xFAD, PS19 and A53T-αSyn-GFP (A53T) mice. Using these various double mutant mice, we tested the effect of mouse APOE CC on different proteinopathies, including Aβ, tau, Aβ-induced tau after paired helical filament (PHF)-tau intracortical injections, and α-syn after preformed fibril (PFF) intracortical and intramuscular injections. We used immunohistochemical, biochemical and behavioral measures to test for protective effects of APOE CC on these different proteinopathies. Heterozygous (Het) and homozygous (Hom) APOE CC mice showed increased plasma cholesterol and triglyceride levels, as seen in humans, but no differences in body or brain weight, or life expectancy. APOE CC decreased Aβ-induced tau pathologies in PHF-tau injected 5xFAD;Hom mice but did not change Aβ-plaque pathology in 5xFAD mice or tau pathology in PS19 mice. Although Aβ levels, tau levels and mouse sex correlated strongly with the behavioral performance, we only detected subtle effects of APOE CC on anxiety-like behaviors in crosses with 5xFAD, PS19 and PHF-tau injected 5xFAD mice. Interestingly, Het and Hom APOE CC mice both showed reduced formation and spread of Lewy pathology in brain after intracortical α-syn PFF injection and reduced formation in spinal cord after α-syn PFF injection into the hindlimb gastrocnemius muscle in A53T mice. Our study emphasizes the protective effects of the APOE CC variant against different proteinopathies important for dementia and movement disorders, including Aβ plaque, tau and α-syn, and suggests that targeting APOE CC could provide new therapeutic strategies for AD, DLB and PD.

DOI: https://doi.org/10.1101/2025.11.05.686857