Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

Chemical Reviews, Год журнала: 2021, Номер 121(4), С. 2545 - 2647

Опубликована: Фев. 5, 2021

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural dynamic characterization all species along pathways from monomers to fibrils challenging by experimental computational means because they involve intrinsically disordered proteins most diseases. Yet understanding how amyloid become toxic challenge developing treatment for these Here we review what computer, vitro, vivo, pharmacological experiments tell us about accumulation deposition oligomers (Aβ, tau), α-synuclein, IAPP, superoxide dismutase 1 proteins, which have been mainstream concept underlying Alzheimer's disease (AD), Parkinson's (PD), type II diabetes (T2D), amyotrophic lateral sclerosis (ALS) research, respectively, years.

Язык: Английский

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Amyloid-type Protein Aggregation and Prion-like Properties of Amyloids

Chemical Reviews, Год журнала: 2021, Номер 121(13), С. 8285 - 8307

Опубликована: Июнь 17, 2021

This review will focus on the process of amyloid-type protein aggregation. Amyloid fibrils are an important hallmark misfolding diseases and therefore have been investigated for decades. Only recently, however, atomic or near-atomic resolution structures elucidated from various in vitro ex vivo obtained fibrils. In parallel, fibril formation has studied under highly artificial but comparatively reproducible conditions. The starts with a summary what is known speculated aggregation experiments. A partially hypothetic selection model be described that may suitable to explain why amyloid look way they do, particular, at least all so far reported high cryo-electron microscopy register, cross-β-sheet mostly consist two protofilaments twisted around each other. An intrinsic feature prion-like nature assemblies. Transferring point view situation not straightforward, hypothetic, leaves many open questions need addressed future.

Язык: Английский

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A guide to studying protein aggregation

FEBS Journal, Год журнала: 2021, Номер 290(3), С. 554 - 583

Опубликована: Дек. 4, 2021

Disrupted protein folding or decreased stability can lead to the accumulation of (partially) un- misfolded proteins, which ultimately cause formation aggregates. Much interest in aggregation is associated with its involvement a wide range human diseases and challenges it poses for large-scale biopharmaceutical manufacturing formulation therapeutic proteins peptides. On other hand, aggregates also be functional, as observed nature, triggered use development biomaterials therapeutics well improvement food characteristics. Thus, unmasking various steps involved critical obtain better understanding underlying mechanism amyloid formation. This knowledge will allow more tailored diagnostic methods treatments amyloid-associated diseases, applications fields new (bio)materials, technology therapeutics. However, complex dynamic nature process makes study challenging. To provide guidance on how analyse aggregation, this review we summarize most commonly investigated aspects some popular corresponding methods.

Язык: Английский

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In-Cell Structural Biology by NMR: The Benefits of the Atomic Scale

Chemical Reviews, Год журнала: 2022, Номер 122(10), С. 9497 - 9570

Опубликована: Март 31, 2022

In-cell structural biology aims at extracting information about proteins or nucleic acids in their native, cellular environment. This emerging field holds great promise and is already providing new facts outlooks of interest both fundamental applied levels. NMR spectroscopy has important contributions on this stage: It brings a broad variety nuclei the atomic scale, which ensures its versatility uniqueness. Here, we detail methods, knowledge, applications biomedical engineering related to in-cell by NMR. We finally propose brief overview main other techniques (EPR, smFRET, cryo-ET, etc.) draw some advisable developments for In era large-scale screenings deep learning, accurate qualitative experimental evidence are as essential ever understand interior life cells. can generate such it does so scale. review meant deliver comprehensive but accessible information, with advanced technical details reflections nature results, future field.

Язык: Английский

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Novel approaches to diagnosis and management of hereditary transthyretin amyloidosis

Journal of Neurology Neurosurgery & Psychiatry, Год журнала: 2022, Номер 93(6), С. 668 - 678

Опубликована: Март 7, 2022

Hereditary transthyretin amyloidosis (ATTRv) is a severe, adult-onset autosomal dominant inherited systemic disease predominantly affecting the peripheral and autonomic nervous system, heart, kidney eyes. ATTRv caused by mutations of (TTR) gene, leading to extracellular deposition amyloid fibrils in multiple organs including system. Typically, neuropathy associated with characterised rapidly progressive disabling sensorimotor axonal early small-fibre involvement. Carpal tunnel syndrome cardiac dysfunction frequently coexist as part phenotype. Although awareness polyneuropathy among neurologists has increased, rate misdiagnosis remains high, resulting significant diagnostic delays accrued disability. A timely definitive diagnosis important, given emergence effective therapies which have revolutionised management amyloidosis. TTR protein stabilisers diflunisal tafamidis can delay progression disease, if treated course. Additionally, gene silencing medications, patisiran inotersen, resulted up 80% reduction production, stabilisation or slight improvement dysfunction, well quality life functional outcomes. The considerable therapeutic advances raised additional challenges, optimisation techniques approaches neuropathy. This review highlights key techniques, current emerging strategies, biomarker development for ATTRv.

Язык: Английский

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Lipid-induced condensate formation from the Alzheimer’s Aβ peptide triggers amyloid aggregation

Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(4)

Опубликована: Янв. 24, 2025

The onset and development of Alzheimer’s disease is linked to the accumulation pathological aggregates formed from normally monomeric amyloid-β peptide within central nervous system. These Aβ are increasingly successfully targeted with clinical therapies at later stages disease, but fundamental molecular steps in early stage that trigger initial nucleation event leading conversion into remain unknown. Here, we show can form biomolecular condensates on lipid bilayers both assays living cells. Our results reveal these significantly accelerate primary step amyloid cascade leads formation aggregates. We contain phospholipids, intrinsically heterogeneous, prone undergo a liquid-to-solid transition fibrils. findings uncover liquid–liquid phase separation behavior very aggregation process.

Язык: Английский

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Fluorescent probes for bioimaging of potential biomarkers in Parkinson's disease

Chemical Society Reviews, Год журнала: 2020, Номер 50(2), С. 1219 - 1250

Опубликована: Дек. 8, 2020

Parkinson's disease (PD), as the second most common neurodegenerative disease, is caused by complex pathological processes and currently remains very difficult to treat. PD brings great distress patients imposes a heavy economic burden on society. The number of growing aging population increases worldwide. Therefore, it crucial develop new tools for aiding early diagnosis treatment PD. significant features involved in include abnormal accumulation α-synuclein, metal ion dyshomeostasis, oxidative stress, mitochondrial dysfunction neurotransmitter deficiencies. In recent years, fluorescent probes have emerged powerful bioimaging tool with potential help understand via detection monitoring features. this review, we comprehensively summarize design working mechanisms along their applications various biomarkers. We also discuss current limitations provide perspectives how these can be overcome better suitable application clinical trials future. hope that review provides valuable information guidance development used clinically contributes efficient drugs

Язык: Английский

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The synergic effect of water and biomolecules in intracellular phase separation

Nature Reviews Chemistry, Год журнала: 2019, Номер 3(9), С. 552 - 561

Опубликована: Июль 25, 2019

Язык: Английский

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Structures of the intrinsically disordered Aβ, tau and α-synuclein proteins in aqueous solution from computer simulations

Biophysical Chemistry, Год журнала: 2020, Номер 264, С. 106421 - 106421

Опубликована: Июнь 30, 2020

Язык: Английский

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Amyloid-β peptide dimers undergo a random coil to β-sheet transition in the aqueous phase but not at the neuronal membrane

Proceedings of the National Academy of Sciences, Год журнала: 2021, Номер 118(39)

Опубликована: Сен. 20, 2021

Significance The aggregation of the amyloid- β peptide (A ) into neurotoxic oligomers is central to development Alzheimer’s disease. One possible source their toxicity results from interactions A with neuronal membrane, damaging membrane integrity and thus neurons. However, molecular details these are unclear. Here, we contrast dimerization in solution at membrane. Our clearly indicate that sugar moieties GM1 sequester by forming key hydrogen bonds peptide, which diverts configuration dimers away -sheet–rich structures. These findings underline importance disease progression provide a nanoscopic basis for its reported neuroprotective effect.

Язык: Английский

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