Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids

Nature, Journal Year: 2023, Volume and Issue: 621(7980), P. 701 - 710

Published: Sept. 27, 2023

Language: Английский

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Structural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 17, 2024

Abstract ATTR amyloidosis is caused by the deposition of transthyretin in form amyloid fibrils virtually every organ body, including heart. This systemic leads to a phenotypic variability that has not been molecularly explained yet. In brain conditions, previous studies suggest an association between clinical phenotype and molecular structures their fibrils. Here we investigate whether there such ATTRv patients carrying mutation I84S. Using cryo-electron microscopy, determined cardiac extracted from three ATTRv-I84S mutation, associated with consistent phenotype. We found each patient, exhibited different local conformations, these variations can co-exist within same fibril. Our finding suggests one disease may associate multiple fibril amyloidoses, calling for further studies.

Language: Английский

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

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 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.

Language: Английский

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Positron emission tomography tracers for synucleinopathies

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: Jan. 5, 2025

Abstract Synucleinopathies, such as Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, are characterized by the aggregation of α-synuclein. Variations in brain distribution allow for differentiation among these diseases facilitate precise clinical diagnosis. However, distinguishing between synucleinopathies Parkinsonism tauopathies poses a challenge, significantly impacting drug development. Therefore, molecular imaging is crucial synucleinopathies, particularly diagnosis, assessment efficacy, disease surveillance. In recent years, advances have led to rapid development α-synuclein-specific tracers positron emission tomography (PET), most which still pre-clinical stages. Interestingly, some share similar compound skeletal structures currently undergoing optimization application. Despite this progress, there remain challenges developing α-synuclein tracers. This review summarizes findings on promising PET discusses representative compounds’ characteristics while offering suggestions further research orientation.

Language: Английский

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Structure–Toxicity Relationship in Intermediate Fibrils from α-Synuclein Condensates

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(15), P. 10537 - 10549

Published: April 3, 2024

The aberrant aggregation of α-synuclein (αS) into amyloid fibrils is associated with a range highly debilitating neurodegenerative conditions, including Parkinson's disease. Although the structural properties mature amyloids αS are currently understood, nature transient protofilaments and that appear during remains elusive. Using solid-state nuclear magnetic resonance (ssNMR), cryogenic electron microscopy (cryo-EM), biophysical methods, we here characterized intermediate forming from liquid-like spherical condensates to adopting structure pathologically observed aggregates. These intermediates, which induce significant levels cytotoxicity when incubated neuronal cells, were found be stabilized by small core in an antiparallel β-sheet conformation, disordered N-terminal region protein remaining available mediate membrane binding. In contrast, subsequently showed different biological properties, low cytotoxicity, rearranged structured embedding also region, reduced propensity interact membrane. characterization these two fibrillar forms αS, use antibodies designed mutants, enabled us clarify role critical elements endowing species ability membranes cytotoxicity.

Language: Английский

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Research Priorities on the Role of α‐Synuclein in Parkinson's Disease Pathogenesis

Movement Disorders, Journal Year: 2024, Volume and Issue: 39(10), P. 1663 - 1678

Published: June 30, 2024

Abstract Various forms of Parkinson's disease, including its common sporadic form, are characterized by prominent α‐synuclein (αSyn) aggregation in affected brain regions. However, the role αSyn pathogenesis and evolution disease remains unclear, despite vast research efforts more than a quarter century. A better understanding αSyn, either primary or secondary, is critical for developing disease‐modifying therapies. Previous attempts to hone this have been challenged experimental limitations, but recent technological advances may facilitate progress. The Scientific Issues Committee International Parkinson Movement Disorder Society (MDS) charged panel experts field discuss current scientific priorities identify strategies with potential breakthrough. © 2024 Author(s). Disorders published Wiley Periodicals LLC on behalf Society.

Language: Английский

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α-Synuclein Strains and Their Relevance to Parkinson’s Disease, Multiple System Atrophy, and Dementia with Lewy Bodies

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(15), P. 12134 - 12134

Published: July 28, 2023

Like many neurodegenerative diseases, Parkinson’s disease (PD) is characterized by the formation of proteinaceous aggregates in brain cells. In PD, those are formed α-synuclein (αSyn) and considered trademark this disease. addition to αSyn pathological aggregation also detected atypical Parkinsonism, including Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), as well neurodegeneration iron accumulation, some cases traumatic injuries, variants Alzheimer’s Collectively, these (and other) disorders referred synucleinopathies, highlighting relation between type protein misfolding/aggregation. Despite relationships, however, synucleinopathies cover a wide range pathologies, present multiplicity symptoms, arise from dysfunctions different neuroanatomical regions cell populations. Strikingly, deposition occurs types cells, oligodendrocytes being mainly affected MSA, while found neurons PD. If multiple factors contribute development pathology, especially slow-developing disorders, common presence aggregation, both marker potential driver disease, puzzling. review, we will focus on comparing DLB, symptomatology molecular description, role contribution each disorder. We particularly recent evidence for involvement conformational strains discuss reciprocal relationship cellular milieu. Moreover, highlight need effective methodologies strainotyping ameliorate diagnosing capabilities therapeutic treatments.

Language: Английский

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On the pH-dependence of α-synuclein amyloid polymorphism and the role of secondary nucleation in seed-based amyloid propagation

eLife, Journal Year: 2024, Volume and Issue: 12

Published: Aug. 28, 2024

The aggregation of the protein α-synuclein is closely associated with several neurodegenerative disorders and as such structures amyloid fibril aggregates have high scientific medical significance. However, there are dozens unique atomic-resolution these aggregates, a highly polymorphic nature fibrils hampers efforts in disease-relevant vitro studies on aggregation. In order to better understand factors that affect polymorph selection, we studied function pH buffer using cryo-EM helical reconstruction. We find physiological range 5.8–7.4, pH-dependent selection between Type 1, 2, 3 polymorphs occurs. Our results indicate even presence seeds, during dependent conditions, attributed non-polymorph-specific secondary nucleation. also uncovered two new occur at 7.0 phosphate-buffered saline. first monofilament 1 resembles structure juvenile-onset synucleinopathy found patient-derived material. second 5 has been recently reported study used diseased tissues seed Taken together, our highlight shallow energy hypersurface can be altered by subtle changes environment, including which shown play major role many cases appears determining factor seeded suggest possibility producing vitro.

Language: Английский

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Molecular rules governing the structural polymorphism of amyloid fibrils in neurodegenerative diseases

Structure, Journal Year: 2023, Volume and Issue: 31(11), P. 1335 - 1347

Published: Aug. 31, 2023

Language: Английский

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Cryo-EM confirms a common fibril fold in the heart of four patients with ATTRwt amyloidosis

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: July 27, 2024

ATTR amyloidosis results from the conversion of transthyretin into amyloid fibrils that deposit in tissues causing organ failure and death. This is facilitated by mutations ATTRv amyloidosis, or aging ATTRwt amyloidosis. exhibits extreme phenotypic variability, whereas presentation consistent predictable. Previously, we found unique structural variabilities cardiac polyneuropathic ATTRv-I84S patients. In contrast, five genotypically different patients with cardiomyopathy mixed phenotypes are structurally homogeneous. To understand fibril structure's impact on phenotype, it necessary to study multiple sharing genotype phenotype. Here show cryo-electron microscopy structures extracted four cardiomyopathic Our confirms they share identical conformations minimal their homogenous clinical presentation. contributes understanding biopathology calls for further studies. Cryo-EM analysis reveals variability. finding biopathology.

Language: Английский

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