O-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology

Nature Chemical Biology, Год журнала: 2024, Номер 20(5), С. 646 - 655

Опубликована: Фев. 12, 2024

Abstract Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer’s Parkinson’s disease, can form different fibril structures or strains with distinct toxic properties, seeding activities pathology. Understanding the determinants contributing to formation of amyloid features could open new avenues for developing disease-specific diagnostics therapies. Here we report that O-GlcNAc modification monomers results core structure, as revealed by cryogenic electron microscopy, diminished activity seeding-based neuronal rodent models disease. Although mechanisms underpinning neutralization O-GlcNAc-modified fibrils remain unclear, our vitro mechanistic studies indicate heat shock interactions inhibit their activity, suggesting may alter interactome ways lead reduce vivo. Our show posttranslational modifications, modification, key pathogenicity.

Язык: Английский

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Structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Март 29, 2024

Abstract The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation alpha-synuclein (Asyn) fibrils in bodies neurites. Here we develop validate a method to amplify Asyn extracted from LBD postmortem tissue samples use solid state nuclear magnetic resonance (SSNMR) studies determine atomic resolution structure. Amplified comprise mixture single protofilament two with very low twist. fold highly similar determined by recent cryo-electron microscopy study for minority population twisted tissue. These results expand structural characterization approaches studying mechanisms, imaging agents therapeutics targeting Asyn.

Язык: Английский

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Phosphorylation and O-GlcNAcylation at the same α-synuclein site generate distinct fibril structures

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Март 27, 2024

Abstract α-Synuclein forms amyloid fibrils that are critical in the progression of Parkinson’s disease and serves as pathological hallmark this condition. Different posttranslational modifications have been identified at multiple sites α-synuclein, influencing its conformation, aggregation function. Here, we investigate how disease-related phosphorylation O-GlcNAcylation same α-synuclein site (S87) affect fibril structure neuropathology. Using semi-synthesis, obtained homogenous monomer with site-specific (pS87) (gS87) S87, respectively. Cryo-EM revealed pS87 gS87 form two distinct structures. The GlcNAc situated S87 establishes interactions K80 E61, inducing a unique iron-like fold molecule on iron handle. Phosphorylation prevents lengthy C-terminal region including residues 73 to 140 from incorporating into core due electrostatic repulsion. Instead, N-terminal half (1–72) takes an arch-like structure. We further show both display reduced neurotoxicity propagation activity compared unmodified fibrils. Our findings demonstrate different can produce structures, which emphasizes link between formation pathology.

Язык: Английский

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Amyloid fibril polymorphism: a challenge for molecular imaging and therapy

Journal of Internal Medicine, Год журнала: 2018, Номер 283(3), С. 218 - 237

Опубликована: Янв. 23, 2018

Abstract The accumulation of misfolded proteins ( MP s), both unique and common, for different diseases is central many chronic degenerative diseases. In certain patients, systemic (e.g. TTR amyloid), in others, this localized to a specific cell type Alzheimer's disease). neurodegenerative diseases, ND s, it noticeable that the progressively spreads throughout nervous system. Our main hypothesis article s are not only markers but also active carriers pathogenicity. Here, we discuss studies from comprehensive molecular approaches aimed at understanding conformational variations (polymorphism) their bearing on spreading toxicity, as well targeting imaging therapy. Neurodegenerative disease ) represents major growing societal challenge, with millions people worldwide suffering or Parkinson's alone. For all current treatment palliative without addressing primary cause curative. Over recent years, particularly shape‐shifting properties pathways have been intensively researched. difficulty has prompted most pharma companies severely downsize system disorder research. Increased academic research pivotal filling void translate basic into tools medical professionals. Recent discoveries drug design against improved model systems study structure, pathology toxicity strongly encourage future along these lines provide an opportunity selective imaging, prognostic diagnosis

Язык: Английский

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How specific are the conformation-specific α-synuclein antibodies? Characterization and validation of 16 α-synuclein conformation-specific antibodies using well-characterized preparations of α-synuclein monomers, fibrils and oligomers with distinct structures and morphology

Neurobiology of Disease, Год журнала: 2020, Номер 146, С. 105086 - 105086

Опубликована: Сен. 22, 2020

Increasing evidence suggests that alpha-synuclein (α-syn) oligomers are obligate intermediates in the pathway involved α-syn fibrillization and Lewy body (LB) formation, may also accumulate within LBs Parkinson's disease (PD) other synucleinopathies. Therefore, development of tools methods to detect quantify has become increasingly crucial for mechanistic studies understand their role PD, develop new diagnostic therapies PD The majority these rely primarily on use aggregation state-specific or conformation-specific antibodies. Given impact data knowledge generated using antibodies shaping foundation directions research, it is thoroughly characterized, specificity ability capture diverse species tested validated. Herein, we describe an antibody characterization validation pipeline allows a systematic investigation well-defined well-characterized preparations various species, including monomers, fibrils, different oligomer characterized by distinct morphological, chemical secondary structure properties. This was used characterize 18 antibodies, 16 which have been reported as conformation- oligomer-specific array techniques, immunoblot analysis (slot blot Western blot), digital ELISA assay single molecule technology surface plasmon resonance. Our results show i) none specific one particular type fibrils; ii) all were be recognized fibrillar α-syn; iii) few showed high fibrils but did not bind monomers. These findings suggest great aggregate-specific do differentiate between thus highlighting importance exercising caution when interpreting obtained underscore critical before therapeutic agents. will only improve quality reproducibility research reduce costs number failures clinic.

Язык: Английский

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