bims-proned 2026-04-26 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–04–26
thirteen papers selected by
Verena Kohler, Umeå University

Co-Aggregation of Amyloidogenic Proteins in Age-Related Neurodegenerative Diseases.
Alpha-synuclein seed amplification assays differentiate synucleinopathies.
Targeting Alpha-Synuclein Aggregation With Chemical Chaperone IP-045: An Approach to Parkinson's Disease Therapy.
Multifunctional Zinc-Tannic Acid Nanoparticles Target α-Synuclein Aggregation and Oxidative Stress in Parkinson's Disease.
Gradual N-terminal truncation of tau dGAE (297-391) reveals the importance of 321-325 sequence for early steps of fibril formation.
Glutaredoxin-1 attenuates transactive response DNA-binding protein 43-induced neurotoxicity by suppressing oxidative stress and transactive response DNA-binding protein 43 aggregation.
Disulfidptosis in Neurodegenerative Diseases: From Redox Imbalance to Neuronal Dysfunction.
Protoporphyrin IX Attenuates Liquid-Liquid Phase Separation of α-Synuclein by Inducing Its Compaction.
Rational Design of a Multivalent RNA Combining Structural Motifs Tailored to Multiple Domains of Fused in Sarcoma for Potent Inhibition of Aggregation.
TNMD BRICHOS domain attenuates tau pathology and memory deficits in a mouse model of tauopathy.
Alzheimer neuropathological change, α-synuclein and transactive response DNA-binding protein of 43 kDa expression in children and young adult brains from forensic autopsies: Value for early measurement of abnormal protein expression prevalence in neurodegenerative diseases.
A ZIF-8-modified electrochemical biosensor for sensitive Aβ aggregation monitoring and Alzheimer's disease drug screening.
Single-molecule detection methods to study alpha-synuclein aggregation in postmortem Parkinson's disease brains.

Ageing Res Rev. 2026 Apr 22. pii: S1568-1637(26)00140-6. [Epub ahead of print] 103148

Co-Aggregation of Amyloidogenic Proteins in Age-Related Neurodegenerative Diseases.

Shaik Basha, Prakruti Prakash Nadkarni, Aparna Ramakrishna Pai, Krishna Kishore Mahato.

  Age-related neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and related dementias, are increasingly understood as multifactorial proteinopathies involving co-aggregation of amyloidogenic proteins such as Tubulin-associated unit protein (Tau), α-synuclein (α-syn), amyloid-β (Aβ), and TAR DNA-binding protein 43 (TDP-43). Rather than acting independently, these proteins often cross-seed, co-localize, and modulate each other's aggregation dynamics and toxicity. This review critically examines the mechanistic and pathological underpinnings of heterotypic protein co-aggregation, integrating biophysical, cellular, animal, and human data. Further, this review proposes a conceptual framework that views neurodegeneration as a network of interacting misfolded proteins shaped by ageing-related changes in lipid membranes, redox balance, proteostasis, and genetic factors. Emphasis is placed on translational opportunities: co-aggregation-specific biomarkers in cerebrospinal fluid and extracellular vesicles, and emerging multi-targeted therapies including immunotherapy, proteostasis modulators, and autophagy-inducing chimeras. This review also discusses the clinical implications of co-pathology in mixed dementias and overlapping disorders. It is therefore time to move beyond the classical one protein-one disease paradigm and embrace models that explicitly incorporate heterotypic co-aggregation, mixed pathologies, and shared vulnerability pathways across ageing-related disorders. By reframing co-aggregation as a central pathogenic mechanism, this review highlights the need for diagnostics and therapeutics that address the interconnectivity of protein misfolding in ageing brains.

Keywords:  Amyloid-beta; Cross-seeding; Parkinson's Disease; Protein Co-Aggregation; Transactive response DNA-binding protein 43; Tubulin-associated unit

DOI:  https://doi.org/10.1016/j.arr.2026.103148
Expert Rev Mol Diagn. 2026 Apr 22. 1-17

Alpha-synuclein seed amplification assays differentiate synucleinopathies.

Wei Dai, Hao Lin, Hengxu Mao, Yaoyun Kuang, Pingyi Xu, Hongyan Li.

   INTRODUCTION: Synucleinopathies are characterized by the misfolding and aggregation of α-synuclein (α-Syn) into pathogenic strains that seed Lewy-body pathology in neurons and/or glial cytoplasmic inclusions in oligodendrocytes. α-syn seed-amplification assays (α-Syn SAAs) detect as little as 20 femtogram of synthetic α-Syn pre-formed fibrils (PFFs) or analogous synthetic aggregates in biospecimens, offering high sensitivity and specificity for synucleinopathies.
AREAS COVERED: We review how distinct α-Syn strains propagate in Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), and we summarize the biophysical and procedural variables that govern SAA kinetics. We aim to identify an optimal means of modulating α-Syn SAA parameters so that each synucleinopathy subtype consistently yields distinct and stable kinetic signatures, thereby facilitating accurate biochemical diagnosis.
EXPERT OPINION: α-Syn SAA holds the potential to become a routine assay for discriminating among synucleinopathy subtypes. Future research should focus on standardizing α-Syn SAA protocols, exploring the detailed mechanisms of distinct α-Syn strains propagation, and developing novel therapeutic strategies based on these insights.

Keywords:  Parkinson’s disease; kinetics; seed amplification assay; synucleinopathies; α-synuclein aggregation

DOI:  https://doi.org/10.1080/14737159.2026.2663033
Drug Dev Res. 2026 May;87(3): e70288

Targeting Alpha-Synuclein Aggregation With Chemical Chaperone IP-045: An Approach to Parkinson's Disease Therapy.

Navpreet Kaur, Rimaljot Singh, Neelima Dhingra, Tanzeer Kaur.

  Protein misfolding and aggregation of alpha-synuclein (α-syn) are central to Parkinson's disease (PD). Current therapies provide only symptomatic relief without addressing α-syn aggregation. Chemical chaperones such as 4-phenylbutyrate (4-PBA) and tauroursodeoxycholic acid (TUDCA) show promise but are limited by toxicity and high dosage requirements. This study aimed to develop a safer, more effective multi-target compound to counter α-syn aggregation and related cellular stress. To design, synthesize, and evaluate a novel multi-target chemical chaperone, IP-045, for inhibiting α-syn aggregation and ameliorating PD pathology. A structure-based virtual screen of >11,000 compounds against the α-syn fibril structure (PDB ID: 6UFR) identified four candidates with favorable pharmacokinetics. In vitro aggregation assays and SHSY5Y cell models assessed anti-aggregation activity, cytotoxicity, and modulation of rotenone-induced α-syn expression, oxidative stress, and ER stress. The lead compound, IP-045 (2-Fluorophenyl 3-(1H-indol-3-yl)propanoate), was synthesized and tested in a rotenone-induced PD rat model through behavioral, histological, and molecular analyses. IP-045 strongly inhibited α-syn aggregation in vitro with minimal cytotoxicity. In cell-based assays, it reduced reactive oxygen species, ER stress markers, and α-syn expression. In vivo, IP-045 improved motor coordination, memory, and cognitive performance. Immunohistochemistry showed reduced Ser129-phosphorylated α-syn and restored tyrosine hydroxylase. IP-045 also suppressed apoptotic and pro-inflammatory markers in the substantia nigra, confirming multi-target neuroprotective activity. IP-045 demonstrated favorable anti-aggregation and neuroprotective effects across in vitro and in vivo models, indicating its potential as a promising lead compound with chaperone-like activity for targeting pathological processes associated with PD. Further pharmacokinetic, toxicity, and mechanistic studies are warranted to support its future therapeutic development.

Keywords:  4‐phenyl butyric acid; Parkinson disease; alpha‐synuclein aggregation; chemical chaperone

DOI:  https://doi.org/10.1002/ddr.70288
Nano Lett. 2026 Apr 18.

Multifunctional Zinc-Tannic Acid Nanoparticles Target α-Synuclein Aggregation and Oxidative Stress in Parkinson's Disease.

Yuhang Li, Shangjie An, Yurong Han, Hongda Wang, Xiue Jiang.

  In Parkinson's disease (PD), the abnormal aggregation of α-synuclein (α-Syn) and oxidative stress form a self-reinforcing vicious cycle that is a key driver of disease progression. To disrupt this pathogenic loop, this study designed and synthesized zinc-tannic acid coordination nanoparticles (Zn-TA NPs). Zn-TA NPs exhibit potent reactive oxygen species (ROS) scavenging capability and can concurrently inhibit α-Syn fibril formation and disaggregate α-Syn fibrils. In cellular models, Zn-TA NPs scavenged ROS, preserved mitochondrial function, and demonstrated neuroprotective effects. In a PD mouse model, treatment with Zn-TA NPs significantly improved motor and cognitive deficits, attenuated dopaminergic neuron loss, and reduced cerebral levels of α-Syn pathological deposition, oxidative stress, and neuroinflammation, without inducing significant systemic toxicity. These findings indicate that Zn-TA NPs exert multitarget neuroprotective effects by synergistically modulating α-Syn aggregation and oxidative stress, offering a novel strategy based on natural polyphenol-metal coordination for the treatment of neurodegenerative diseases.

Keywords:  Parkinson’s disease; antioxidant; metal-phenolic nanoparticles; protein aggregation; α-synuclein

DOI:  https://doi.org/10.1021/acs.nanolett.6c00790
Int J Biol Macromol. 2026 Apr 17. pii: S0141-8130(26)01992-6. [Epub ahead of print]362 152066

Gradual N-terminal truncation of tau dGAE (297-391) reveals the importance of 321-325 sequence for early steps of fibril formation.

Stefana Njemoga, Petra Majerova, Juraj Piestansky, Zuzana Gazova, Pavel Kaderavek, Exequiel E Barrera, Zuzana Bednarikova, Ondrej Cehlar.

  The pathological conversion of intrinsically disordered proteins into β-sheet-rich amyloid filaments is a hallmark of numerous neurodegenerative disorders. In the case of tau protein, misfolding into aggregation-prone species can be promoted by truncation, motivating the present study. We employed an integrative approach combining established experimental techniques, including AFM and ThT fluorescence assay, with MD simulations to study amyloidogenic propensities of five tau truncation variants in the presence of aggregation inducers in vitro. The experimental observations were further validated by CD and NMR spectroscopy. Our experiments demonstrated that tau variants exhibit distinct amyloidogenic propensities. Tau variant spanning residues 321-391 (numbered according to the longest CNS tau isoform 1-441) represents the minimal E391-truncated construct capable of amyloid aggregation in vitro, whereas the shorter 326-391 variant failed to form fibrillar assemblies, even in the presence of aggregation inducers. All-atom (AA) MD simulations highlighted the importance of hairpin-like structural motifs during the early stages of aggregation, which appear to template subsequent fibril growth and are preferentially adopted by the Tau321-391 variant. In contrast, coarse-grained (CG) simulations revealed a pronounced α-helical propensity in Tau321-391, particularly at the N-terminal region. This elevated N-terminal helicity constitutes the most prominent structural distinction between the aggregation-competent and aggregation-incompetent variants. In both AA and CG MD simulations, the structural transitions of tau were driven by amyloid-nucleating sequence motifs, including the G-motif, PHF6**, and PAM4. Despite sharing these amyloidogenic regions, the Tau326-391 variant lacks the intrinsic amyloid propensity required to undergo productive self-assembly into ordered amyloid fibrils.

Keywords:  Amyloid aggregation; Amyloidogenic motifs; MD simulation; Tau protein

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152066
Neuroreport. 2026 Apr 22.

Glutaredoxin-1 attenuates transactive response DNA-binding protein 43-induced neurotoxicity by suppressing oxidative stress and transactive response DNA-binding protein 43 aggregation.

Ji Min Lee, Eugene Bok, Sang Ryong Kim, Jaekwang Kim.

   OBJECTIVE: Cytoplasmic aggregation of transactive response DNA-binding protein 43 (TDP-43) represents pathological hallmarks of TDP-43 proteinopathies. Accumulating evidence indicates that oxidative stress plays a pivotal role in these disorders by promoting TDP-43 aggregation and subsequent neurotoxicity. Glutaredoxin-1 (Grx1) is a key antioxidant enzyme that maintains cellular redox homeostasis. In this study, we investigated the role of Grx1 in TDP-43 proteinopathy.
METHODS: We examined the effects of Grx1 in neuro-2a cells expressing human wild-type TDP-43 (N2a-hTDP-43), a cellular model of TDP-43 proteinopathy characterized by increased oxidative stress, TDP-43 aggregation, and neurotoxicity.
RESULTS: In N2a-hTDP-43 cells, Grx1 expression was increased in parallel with elevated oxidative stress. Increasing Grx1 significantly suppresses intracellular oxidative stress and cytoplasmic TDP-43 aggregation in N2a-hTDP-43 cells. Notably, increasing Grx1 significantly reduces cleaved caspase-3 levels in N2a-hTDP-43 cells, indicating reduced neurotoxicity.
CONCLUSION: Collectively, our findings demonstrate that Grx1 attenuates neurotoxicity by suppressing oxidative stress and TDP-43 aggregation, highlighting its potential as a therapeutic target for TDP-43 proteinopathies.

Keywords:  cytoplasmic aggregation; glutaredoxin-1; oxidative stress; transactive response DNA-binding protein 43 proteinopathy

DOI:  https://doi.org/10.1097/WNR.0000000000002266
Behav Brain Res. 2026 Apr 22. pii: S0166-4328(26)00218-4. [Epub ahead of print] 116242

Disulfidptosis in Neurodegenerative Diseases: From Redox Imbalance to Neuronal Dysfunction.

Caizhen Shi, Kunpeng Jia, Yanjie Guo, Shenghao Qian, Bingbing Wang, Yue Qiu, Li Dan, Zhuokun Dang, Kun Xue, Feng Gao, Lin Zhao.

  Disulfidptosis is a recently identified form of regulated cell death driven by disulfide stress and cytoskeletal collapse under conditions of impaired reducing capacity. Neurodegenerative diseases (NDs), including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, are characterized by oxidative stress, mitochondrial dysfunction, metabolic impairment, protein aggregation, and cytoskeletal instability-features that may provide a permissive intracellular context for disulfidptosis. However, its occurrence and pathological relevance in these disorders remain incompletely understood. In this review, we examine the potential involvement of disulfidptosis in neurodegenerative diseases from a disease-centered perspective. We emphasize that current evidence is largely indirect and based on mechanistic overlap rather than direct experimental validation in neural systems. Accordingly, we distinguish between direct evidence, indirect mechanistic support, and pathophysiological plausibility. We further discuss cell-type-specific susceptibility across neurons and glial cells, analyze its relationship with other cell death pathways, and consider potential therapeutic implications. Overall, disulfidptosis is best regarded as a context-dependent and emerging mechanism that may contribute to neuronal vulnerability under specific metabolic and redox constraints. Clarifying its disease relevance will be essential for determining its significance in neurodegeneration and its potential as a therapeutic target.

Keywords:  cell death; disulfidptosis; mitochondria; neurodegenerative diseases; protein aggregation; redox imbalance

DOI:  https://doi.org/10.1016/j.bbr.2026.116242
J Phys Chem Lett. 2026 Apr 20.

Protoporphyrin IX Attenuates Liquid-Liquid Phase Separation of α-Synuclein by Inducing Its Compaction.

Souradip Paul, Satadru Chatterjee, Tathagata Acharya, Abhishek Mazumder, Krishnananda Chattopadhyay.

α-Synuclein (αS), a neuronal intrinsically disordered protein, forms pathogenic amyloid fibrils, a hallmark of Parkinson's disease. Recent work shows that formation of liquid-like αS condensates can accelerate the generation of fibrils, and therefore, targeting the liquid-like phase separation process can provide a novel route to disrupt αS amyloid formation. Here, we report that endogenous small molecule protoporphyrin IX (PPIX) prevents αS droplet formation by shutting down early events in this process. Using ensemble and single-molecule fluorescence techniques, we show that binding of PPIX to αS results in a collapsed conformation. Live-cell imaging and single-cell point fluorescence correlation spectroscopy revealed PPIX mitigates αS condensate formation in cells. In addition, density functional theory calculations indicate the high dipole character of PPIX, highlighting a critical role of additional weak electrostatic interactions in αS binding. Our work provides the mechanistic underpinnings of PPIX-mediated suppression of αS LLPS and establishes PPIX's therapeutic potential for αS-related synucleinopathies.

DOI: https://doi.org/10.1021/acs.jpclett.6c00339
Chembiochem. 2026 Apr 28. 27(8): e202500568

Rational Design of a Multivalent RNA Combining Structural Motifs Tailored to Multiple Domains of Fused in Sarcoma for Potent Inhibition of Aggregation.

Nobuaki Kuroiwa, Fumika Sakaue, Motoki Miura, Ayano Go, Ryo Iwase, Rintaro Iwata Hara, Nobuo Sanjo, Kumiko Ui-Tei, Takanori Yokota.

  Fused in sarcoma (FUS) is an RNA-binding protein whose pathological aggregation, driven by aberrant phase separation, is implicated in amyotrophic lateral sclerosis (ALS). Although RNA molecules can modulate the FUS phase behavior, identifying highly effective sequences remains challenging because of FUS's multiple low-specificity RNA-binding domains. In this study, we rationally designed a 65-mer RNA, U1'+TERRA, by combining a stem-loop-GGU motif and a G-quadruplex (G4) structure, each known to interact with distinct FUS domains. U1'+TERRA exhibited strong binding affinity and effectively inhibited FUS aggregation in vitro. We introduced 2'-O-methyl modifications, generating (U1'+TERRA)-2'-OMe, which retained structural integrity and demonstrated resistance to nuclease degradation to enhance biological stability. Notably, (U1'+TERRA)-2'-OMe suppressed FUS aggregation even at a low concentration. These findings suggested that multivalent RNA constructs with rationally arranged motifs can serve as potent inhibitors of FUS aggregation. Our approach highlights the potential of structure-guided RNA engineering for the development of nucleic acid therapeutics targeting RNA-binding proteins involved in neurodegenerative diseases, such as ALS.

Keywords:  G‐quadruplex; aggregation; amyotrophic lateral sclerosis (ALS); fused in sarcoma (FUS); phase separation

DOI:  https://doi.org/10.1002/cbic.202500568
Cell Death Dis. 2026 Apr 24.

TNMD BRICHOS domain attenuates tau pathology and memory deficits in a mouse model of tauopathy.

Dandan Su, Huina Li, Lina Pan, Honggui Huang, Tingting Xiao, Guiqin Chen, Wei Tan, Lihong Bu, Zhentao Zhang.

The aberrant aggregation of tau leads to loss of its physiological functions and gain of toxic functions, and plays a crucial role in the pathogenesis of tauopathies including Alzheimer's disease (AD). Targeting tau aggregation is considered a promising strategy for treating tauopathies. The BRICHOS family consists of a variety of proteins containing the BRICHOS domain. Certain endogenous BRICHOS domains may inhibit the pathological aggregation of disease-associated proteins. However, the effects of the BRICHOS domains on tau aggregation remain unknown. Here we revealed that BRICHOS domains from integral membrane protein 2B (ITM2B), tenomodulin (TNMD), and out at first (OAF) bind to tau and inhibit its aggregation in vitro. Intravenous administration of TNMD BRICHOS alleviates tau aggregation, synaptic dysfunction, and memory deficits in Tau P301S transgenic mice. Thus, TNMD BRICHOS may serve as a potential therapeutic approach for the development of treatments for tauopathies.

DOI: https://doi.org/10.1038/s41419-026-08749-3
J Neuropathol Exp Neurol. 2026 Apr 20. pii: nlag028. [Epub ahead of print]

Alzheimer neuropathological change, α-synuclein and transactive response DNA-binding protein of 43 kDa expression in children and young adult brains from forensic autopsies: Value for early measurement of abnormal protein expression prevalence in neurodegenerative diseases.

Lilian Calderón-Garcidueñas, Ozkan Ufuk Nalbantoglu, Angélica González-Maciel, Ricardo Torres-Jardón.

  Alzheimer disease (AD) neuropathologic change (ADNPC), Parkinson disease (PD) α-synuclein (α-Syn), and TAR DNA-binding protein 43 (TDP-43) pathology overlap in a continuum in fine particulate matter (PM2.5)-exposed Metropolitan Mexico City (MMC) children and young adult forensic autopsy brains. This report focuses on a forensic targeted immunohistochemistry protocol to assess ADNPC, α-Syn and TDP-43 in ≤40y subjects, and to define their relationship with cumulative PM2.5 (CPM) exposures. We proposed an early measurement of abnormal protein expression to evaluate neurodegenerative disease prevalence in exposed PM2.5 urban young populations. We studied 189 autopsies average age 26±10y, including 179 MMC ≤40y olds and 10 low pollution controls. Among MMC adults 18-40y, 11.3% exhibited ADNPC alone; 50% had ADNPC + PD, 32.0% had ADNPC + PD + TDP-43 and 6.7% had ADNPC + TDP-43 pathology. In 37 children (13.0±4.8y), 24.3% had ADNPC, 37.8% had ADNPC + PD, 32.4% had ADNPC + PD + TDP-43; 5.4% had ADNPC + TDP-43 pathology. The overlapping children's neuropathology was documented under low CPM. We suggest that measurements of abnormal protein expression to evaluate neurodegenerative disease in young PM2.5-exposed young urban populations in US autopsies will define the prevalence and overlap of early neurodegenerative biological markers. This information guide preventive medicine, health services, environmental PM2.5 emission control and early neuroprotection from potentially preventable air pollution-associated neurodegenerative diseases.

Keywords:  Parkinson and TDP-43 pathology; fine particulate matter PM2.5; pediatric Alzheimer; pediatric neurodegeneration; ultrafine PM; urban and rural environmental pollution

DOI:  https://doi.org/10.1093/jnen/nlag028
RSC Adv. 2026 Apr 20. 16(23): 20855-20865

A ZIF-8-modified electrochemical biosensor for sensitive Aβ aggregation monitoring and Alzheimer's disease drug screening.

Shang-Chi Chien, Yin-Chen Chien, Hung-Ju Wang, Jung-Chih Chen.

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder driven by the abnormal aggregation of β-amyloid (Aβ) into oligomers, fibrils, and plaques. Current therapeutic strategies primarily alleviate symptoms but struggle to prevent aggregation due to the dynamic nature of Aβ species and prolonged drug development cycles. Sensitive and real-time monitoring of Aβ structural transitions is therefore essential for understanding disease progression and evaluating potential inhibitors. In this study, we developed a ZIF-8-modified electrochemical biosensor capable of translating Aβ42 conformational changes into quantifiable current signals, providing a promising platform for monitoring dynamic aggregation. The aggregation behavior of Aβ42 was systematically characterized using dynamic light scattering (DLS), electrochemical measurements, and Thioflavin T (ThT) fluorescence combined with ultrafiltration. A critical transition from the lag to the growth phase was observed at 24 h, with aggregates exceeding ∼60 nm undergoing irreversible fibrillization. The ZIF-8-modified electrochemical sensor detected early-stage structural rearrangements with superior sensitivity compared to conventional ThT fluorescence, revealing subtle oligomer formation. Quantitative current measurements allowed continuous monitoring of aggregation kinetics, highlighting the temporal resolution of the platform. Validation experiments with curcumin treatment demonstrated strong inhibitory effects between 18 and 24 h, delaying fibrillization, reducing late-stage β-sheet accumulation, and decreasing aggregate size by approximately 25%. In addition, the sensor successfully distinguished minor differences in structural transitions under varying inhibitor concentrations, demonstrating its capability for high-resolution, real-time assessment of aggregation dynamics and drug efficacy. This ZIF-8-modified electrochemical biosensor provides high-sensitivity, dynamic monitoring of Aβ42 aggregation and drug-induced inhibition, offering a valuable tool for mechanistic studies of protein aggregation pathology. By enabling early detection of structural transitions and real-time evaluation of inhibitors, this platform has the potential to accelerate therapeutic screening and improve the development of effective interventions for AD.

DOI: https://doi.org/10.1039/d6ra00907g
Cell Rep Methods. 2026 Apr 23. pii: S2667-2375(26)00118-9. [Epub ahead of print] 101418

Single-molecule detection methods to study alpha-synuclein aggregation in postmortem Parkinson's disease brains.

Emre Fertan, John S H Danial, Stephen Neame, Jeff Y L Lam, Matthew W Cotton, Melanie Burke, Zengjie Xia, Yunzhao Wu, Ben Powney, Yoichi Imaizumi, Annelies Quaegebeur, Georg Meisl, James Staddon, David Klenerman.

  Nanoscopic aggregates of alpha-synuclein (ɑSyn) have been observed in Parkinson's disease (PD). However, the processes that occur in vivo leading to the formation of these small aggregates are not well understood. We used ultra-sensitive single-molecule methods, including single molecule array (SIMOA), and super-resolution microscopy to quantify and characterize ɑSyn aggregates harvested from human brain samples, alongside a mouse model of synucleinopathy, using different tissue processing methods. While aggregate numbers did not differ between PD and control samples, larger aggregates were detected in PD brain samples. Moreover, different sub-populations of aggregates were obtained by different extraction methods, with diffusible and membrane-bound aggregates producing a more pronounced difference between disease and control samples. Our data suggest that ɑSyn aggregates slowly in the brain, leading to formation of larger aggregates in a sub-set of cells.

Keywords:  CP: imaging; CP: neuroscience; DNA-PAINT; SIMOA; Triton X-100; data modeling; diffusible aggregate; extraction; mouse model; sarkosyl; single-molecule detection; soluble aggregate

DOI:  https://doi.org/10.1016/j.crmeth.2026.101418