Opportunities and challenges of alpha-synuclein as a potential biomarker for Parkinson’s disease and other synucleinopathies

npj Parkinson s Disease, Journal Year: 2022, Volume and Issue: 8(1)

Published: July 22, 2022

Abstract Parkinson’s disease (PD), the second most common progressive neurodegenerative disease, develops and progresses for 10–15 years before clinical diagnostic symptoms of are manifested. Furthermore, several aspects PD pathology overlap with other diseases (NDDs) linked to alpha-synuclein (aSyn) aggregation, also called synucleinopathies. Therefore, there is an urgent need discover validate early prognostic markers that reflect pathophysiology, progression, severity, potential differences in mechanisms between NDDs. The close association aSyn development synucleinopathies, along identification species biological fluids, has led increasing interest as biomarkers diagnosis differentiate it from In this review, we (1) provide overview progress toward mapping distribution brain, peripheral tissues, fluids; (2) present comparative critical analysis previous studies measured total well such modified aggregated forms different (3) highlight conceptual technical gaps challenges could hinder validation reliable biomarkers; (4) outline a series recommendations address these challenges. Finally, propose combined biomarker approach based on integrating biochemical, aggregation structure features aSyn, addition neurodegeneration. We believe capturing diversity essential develop robust assays diagnostics detection, patient stratification, monitoring differentiation This transform trial design implementation, accelerate new therapies, improve decisions treatment strategies.

Language: Английский

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Oxidative damage in neurodegeneration: roles in the pathogenesis and progression of Alzheimer disease

Physiological Reviews, Journal Year: 2023, Volume and Issue: 104(1), P. 103 - 197

Published: Oct. 16, 2023

Alzheimer disease (AD) is associated with multiple etiologies and pathological mechanisms, among which oxidative stress (OS) appears as a major determinant. Intriguingly, OS arises in various pathways regulating brain functions, it seems to link different hypotheses mechanisms of AD neuropathology high fidelity. The particularly vulnerable damage, mainly because its unique lipid composition, resulting an amplified cascade redox reactions that target several cellular components/functions ultimately leading neurodegeneration. present review highlights the “OS hypothesis AD,” including amyloid beta-peptide-associated role protein oxidation unraveled by proteomics, antioxidant strategies have been investigated modulate progression AD. Collected studies from our groups others contributed unraveling close relationships between perturbation homeostasis elucidating redox-regulated events potentially involved both pathogenesis However, complexity requires in-depth understanding intracellular affecting relevant for functions. This crucial developing pharmacological targeting OS-mediated toxicity may contribute slow well improve quality life persons this severe dementing disorder.

Language: Английский

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Heterotypic electrostatic interactions control complex phase separation of tau and prion into multiphasic condensates and co-aggregates

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(2)

Published: Jan. 3, 2023

Biomolecular condensates formed via phase separation of proteins and nucleic acids are thought to perform a wide range critical cellular functions by maintaining spatiotemporal regulation organizing intracellular biochemistry. However, aberrant transitions implicated in multitude human diseases. Here, we demonstrate that two neuronal proteins, namely tau prion, undergo complex coacervation driven domain-specific electrostatic interactions yield highly dynamic, mesoscopic liquid-like droplets. The acidic N-terminal segment interacts electrostatically with the polybasic intrinsically disordered prion protein (PrP). We employed unique combination time-resolved tools encompass several orders magnitude timescales ranging from nanoseconds seconds. These studies unveil an intriguing symphony molecular events associated formation heterotypic comprising ephemeral, domain-specific, short-range nanoclusters. Our results reveal these can be tuned RNA stoichiometry-dependent manner resulting reversible, multiphasic, immiscible, ternary different morphologies core-shell nested This system exhibits typical three-regime behavior reminiscent other membraneless organelles including nucleolar condensates. also show upon aging, tau:PrP droplets gradually convert into solid-like co-assemblies sequestration persistent intermolecular interactions. vibrational Raman conjunction atomic force microscopy multi-color fluorescence imaging presence amorphous amyloid-like co-aggregates maturation. findings provide mechanistic underpinnings overlapping neuropathology involving PrP highlight broader biological role physiology disease.

Language: Английский

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Mitochondria in Alzheimer’s Disease Pathogenesis

Life, Journal Year: 2024, Volume and Issue: 14(2), P. 196 - 196

Published: Jan. 30, 2024

Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder that primarily affects persons aged 65 years above. It causes dementia with memory loss deterioration in thinking language skills. AD characterized by specific pathology resulting from the accumulation brain of extracellular plaques amyloid-β intracellular tangles phosphorylated tau. The importance mitochondrial dysfunction pathogenesis, while previously underrecognized, now more appreciated. Mitochondria are an essential organelle involved cellular bioenergetics signaling pathways. Mitochondrial processes crucial for synaptic activity such as mitophagy, trafficking, fission, fusion dysregulated brain. Excess fission fragmentation yield mitochondria low energy production. Reduced glucose metabolism also observed hypometabolic state, particularly temporo-parietal regions. This review addresses multiple ways which abnormal structure function contribute to AD. Disruption electron transport chain ATP production neurotoxic because cells have disproportionately high demands. In addition, oxidative stress, extremely damaging nerve cells, rises dramatically dyshomeostasis. Restoring health may be viable approach treatment.

Language: Английский

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Quercetin-functionalized nanomaterials: Innovative therapeutic avenues for Alzheimer's disease management

Ageing Research Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 102665 - 102665

Published: Jan. 1, 2025

Language: Английский

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Current Progress and Future Directions in Non-Alzheimer’s Disease Tau PET Tracers

ACS Chemical Neuroscience, Journal Year: 2025, Volume and Issue: 16(2), P. 111 - 127

Published: Jan. 6, 2025

Alzheimer's disease (AD) and non-AD tauopathies are dominant public health issues driven by several factors, especially in the aging population. The discovery of first-generation radiotracers, including [18F]FDDNP, [11C]PBB3, [18F]flortaucipir, [18F]THK series, for vivo detection has marked a significant breakthrough fields neuroscience radiopharmaceuticals, creating robust new category labeled compounds: tau positron emission tomography (PET) tracers. Subsequently, other PET tracers with improved binding properties have been developed using various chemical scaffolds to target three-repeat/four-repeat (3R/4R) folds AD. In 2020, [18F]flortaucipir was approved U.S. Food Drug Administration imaging pathology adult patients cognitive deficits undergoing evaluation Despite remarkable progress development AD tracers, agents rare (4R [predominantly expressing 4R isoform], involved progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, globular glial tauopathy, 3R such as Pick's disease) remain substantially underdeveloped. this review, we discuss recent tracer development, particular emphasis on clinically validated their potential use tauopathies. Additionally, highlight critical need further specifically designed tauopathies, an area that remains significantly underexplored despite its importance advancing understanding diagnosis these disorders.

Language: Английский

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Targeting protein kinases for the treatment of Alzheimer's disease: Recent progress and future perspectives

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 261, P. 115817 - 115817

Published: Sept. 14, 2023

Language: Английский

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Chemical Features of Polyanions Modulate Tau Aggregation and Conformational States

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(7), P. 3926 - 3936

Published: Feb. 8, 2023

The aggregation of tau into insoluble fibrils is a defining feature neurodegenerative tauopathies. However, has positive overall charge and highly soluble; so, polyanions, such as heparin, are typically required to promote its in vitro. There dozens polyanions living systems, it not clear which ones might this process. Here, we systematically measure the ability 37 diverse, anionic biomolecules initiate using either wild-type (WT) or disease-associated P301S mutant. We find that from many different structural classes can fibril formation sensitive greater number (28/37) than WT (21/37). also some preferentially reduce lag time reactions, while others enhance elongation rate, suggesting they act on partially distinct steps. From resulting structure–activity relationships, valency polyanion seems be an important chemical anions with low tend weaker inducers, even at same charge. Finally, identity influences morphology based electron microscopy limited proteolysis. These results provide insights crucial role polyanion–tau interactions modulating conformational dynamics implications for understanding landscape complex cellular environment.

Language: Английский

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Sensitive label-free detection of the biomarker phosphorylated tau−217 protein in Alzheimer's disease using a graphene-based solution-gated field effect transistor

Biosensors and Bioelectronics, Journal Year: 2023, Volume and Issue: 228, P. 115174 - 115174

Published: March 12, 2023

Language: Английский

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Nasal tau immunotherapy clears intracellular tau pathology and improves cognitive functions in aged tauopathy mice

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(754)

Published: July 3, 2024

Pathological tau aggregates cause cognitive decline in neurodegenerative tauopathies, including Alzheimer’s disease (AD). These are prevalent within intracellular compartments. Current immunotherapies have shown limited efficacy clearing and improving cognition clinical trials. In this study, we developed toxic conformation–specific monoclonal antibody-2 (TTCM2), which selectively recognized pathological brain tissues from patients with AD, dementia Lewy bodies (DLB), progressive supranuclear palsy (PSP). TTCM2 potently inhibited tau-seeding activity, an essential mechanism underlying tauopathy progression. To effectively target ensure rapid delivery to the brain, was loaded micelles (TTCM2-ms) administered through intranasal route. We found that intranasally TTCM2-ms efficiently entered hTau-tauopathy mice, targeting Moreover, a single dose of cleared tau, elevated synaptic proteins, improved functions aged mice. Mechanistic studies revealed intracellular, synaptic, seed-competent tripartite motif-containing 21 (TRIM21), antibody receptor E3 ubiquitin ligase known facilitate proteasomal degradation cytosolic antibody-bound proteins. TRIM21 be for TTCM2-ms–mediated clearance pathology. Our study collectively provides evidence effectiveness nasal immunotherapy pathology enhancing This could valuable designing effective AD other tauopathies.

Language: Английский

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