Inhibition of toxic metal-alpha synuclein interactions by human serum albumin

Chemical Science, Journal Year: 2024, Volume and Issue: 15(10), P. 3502 - 3515

Published: Jan. 1, 2024

Human serum albumin (HSA) not only serves as a crucial carrier of various ligands but also modulates the aggregation amyloidogenic proteins, including alpha synuclein (αSyn), which is associated with Parkinson's disease and other synucleinopathies.

Language: Английский

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Exosomes as Biomarkers and Therapeutic Agents in Neurodegenerative Diseases: Current Insights and Future Directions

Molecular Neurobiology, Journal Year: 2025, Volume and Issue: unknown

Published: March 17, 2025

Abstract Neurodegenerative diseases (NDs) like Alzheimer’s, Parkinson’s, and ALS rank among the most challenging global health issues, marked by substantial obstacles in early diagnosis effective treatment. Current diagnostic techniques frequently demonstrate inadequate sensitivity specificity, whilst conventional treatment strategies encounter challenges related to restricted bioavailability insufficient blood–brain barrier (BBB) permeability. Recently, exosomes—nanoscale vesicles packed with proteins, RNAs, lipids—have emerged as promising agents potential reshape therapeutic approaches these diseases. Unlike drug carriers, they naturally traverse BBB can deliver bioactive molecules affected neural cells. Their molecular cargo influence cell signaling, reduce neuroinflammation, potentially slow neurodegenerative progression. Moreover, exosomes serve non-invasive biomarkers, enabling precise while allowing real-time disease monitoring. Additionally, engineered exosomes, loaded molecules, enhance this capability targeting diseased neurons overcoming barriers. By offering enhanced reduced immunogenicity, an ability bypass physiological limitations, exosome-based present a transformative advantage over existing approaches. This review examines multifaceted role of NDDs, emphasizing their capabilities, intrinsic functions, advanced vehicles.

Language: Английский

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Salt-Induced Membrane-Bound Conformation of the NAC Domain of α-Synuclein Leads to Structural Polymorphism of Amyloid Fibrils

Biomolecules, Journal Year: 2025, Volume and Issue: 15(4), P. 506 - 506

Published: March 31, 2025

α-Synuclein (αS) interacts with lipid membranes in neurons to form amyloid fibrils that contribute Parkinson's disease, and its non-amyloid-β component domain is critical the fibrillation. In this study, salt (NaCl) effect on membrane interaction fibril formation of αS57-102 peptide (containing domain) was characterized at molecular level because exhibited structural polymorphism two morphologies (thin thick) presence NaCl but showed one morphology (thin) absence NaCl. The membrane-bound conformation (before fibrillation) had helical regions (first second) regardless salt, length first region largely shortened when present, exposing hydrophobic area solvent. exposed induced distinct pathways nucleation, depending molar ratios free αS57-102: from association other assembly among αS57-102. differences mainly affected β-strand orientation content within conformations, probably contributing thickness degree, leading polymorphism.

Language: Английский

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Toward a molecular mechanism for the interaction of ATP with alpha-synuclein

Chemical Science, Journal Year: 2023, Volume and Issue: 14(36), P. 9933 - 9942

Published: Jan. 1, 2023

The ability of Adenosine Triphosphate (ATP) to modulate protein solubility establishes a critical link between ATP homeostasis and proteinopathies, such as Parkinson's (PD). most significant risk factor for PD is aging, levels decline dramatically with age. However, the mechanism by which interacts alpha-synuclein (αS), whose aggregation characteristic PD, currently not fully understood, ATP's effect on αS aggregation. Here, we use nuclear magnetic resonance spectroscopy well fluorescence, dynamic light scattering microscopy show that affects multiple species in self-association cascade. triphosphate moiety disrupts long-range electrostatic intramolecular contacts monomers enhance initial aggregation, while also inhibiting formation late-stage β-sheet fibrils disrupting monomer-fibril interactions. These effects are modulated magnesium ions early onset PD-related mutations, suggesting loss hydrotropic function fibrillization may play role etiology.

Language: Английский

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α-Synuclein and Mitochondria: Probing the Dynamics of Disordered Membrane-protein Regions Using Solid-State Nuclear Magnetic Resonance

JACS Au, Journal Year: 2024, Volume and Issue: 4(6), P. 2372 - 2380

Published: May 28, 2024

The characterization of intrinsically disordered regions (IDRs) in membrane-associated proteins is crucial importance to elucidate key biochemical processes, including cellular signaling, drug targeting, or the role post-translational modifications. These protein pose significant challenges powerful analytical techniques molecular structural investigations. We here applied magic angle spinning solid-state nuclear magnetic resonance quantitatively probe dynamics IDRs membrane-bound α-synuclein (αS), a whose aggregation associated with Parkinson's disease (PD). focused on mitochondrial binding αS, an interaction that has functional and pathological relevance neuronal cells considered for underlying mechanisms PD. Transverse longitudinal 15N relaxation revealed dynamical properties αS bound outer membrane (OMM) are different from those cytosolic state, thus indicating generally not interact fact affected by spatial proximity lipid bilayer. Moreover, changes composition OMM dyshomeostasis PD were found significantly perturb topology state αS. Taken together, our data underline characterizing achieve accurate understanding these elusive play numerous processes occurring surfaces.

Language: Английский

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Reply to Matters Arising: In vivo effects of the alpha-synuclein misfolding inhibitor minzasolmin supports clinical development in Parkinson’s disease

npj Parkinson s Disease, Journal Year: 2024, Volume and Issue: 10(1)

Published: March 14, 2024

Language: Английский

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