Biological definitions of synucleinopathies should be anchored in clinical trajectories and encompass the complex biology of the disease

Journal of Parkinson s Disease, Год журнала: 2025, Номер unknown

Опубликована: Фев. 4, 2025

Recently, two proposals for defining Parkinson's disease and its related pathogenic processes have been published. In this viewpoint, we discuss the primary drivers behind these efforts, future directions, challenges that must be addressed. While finding biomarkers is a mandatory step better precision medicine optimal patient stratification in therapeutic trials, argue biological definition of based on single biomarker will struggle to account complexity mechanisms involved developing disease. Additionally, asymptomatic patients should rely thorough understanding patients’ clinical trajectories, which currently not case synucleinopathies.

Язык: Английский

Local Ionic Conditions Modulate the Aggregation Propensity and Influence the Structural Polymorphism of α-Synuclein

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Апрель 10, 2025

Parkinson's disease (PD) is linked to the aggregation of intrinsically disordered protein α-synuclein (aSyn), but precise triggers and mechanisms driving this process remain unclear. Local environmental factors, such as ion concentrations, can influence aSyn's conformational ensemble its tendency aggregate. In study, we explore how physiologically relevant ions, mainly Ca2+ Na+, affect aSyn aggregation, monomer structural dynamics, fibril polymorphism. ThT fluorescence assays show that all ions speed up with having strongest effect. Using heteronuclear single quantum correlation nuclear magnetic resonance (1H-15N HSQC NMR) spectroscopy, validate binds at C-terminus while Na+ interacts nonspecifically across sequence. Small-angle neutron scattering (SANS) hydrogen-deuterium exchange mass spectrometry (HDX-MS) leads more extended structures, results in moderate extension. Molecular dynamics (MD) simulations support this, showing increases extension between NAC region C-terminus, whereas biases toward a moderately elongated structure. MD also shows water persistence times hydration shell, indicating propensity due combination bias solvent mobility. Atomic force microscopy (AFM) points formation distinct polymorphs under different ionic conditions, suggesting ion-induced changes contribute diversity structures. These findings underscore pivotal local milieu shaping structure aSyn, offering insights into molecular underpinnings PD potential therapeutic strategies targeting dynamics.

Язык: Английский

Local ionic conditions modulate the aggregation propensity and influence the structural polymorphism of alpha-synuclein

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 3, 2024

ABSTRACT Parkinson’s Disease (PD) is characterized by the aggregation of alpha-synuclein (aSyn), a presynaptic protein that transitions from disordered monomer into beta-sheet rich amyloid fibrils. The precise triggers and mechanisms underlying aSyn misfolding remain unclear, hindering development effective therapeutics. Monomeric an intrinsically (IDP) with high conformational flexibility. Local environmental factors, such as ion concentrations, can influence ensemble aSyn, impacting its propensity resulting in fibril polymorphism. In this study, we explore impact physiologically relevant ions, mainly Ca 2+ Na + , on kinetics, structural dynamics, polymorphism aSyn. Using ThT fluorescence assays, demonstrate all ions accelerate aggregation, having most significant effect. Heteronuclear Single Quantum Correlation Nuclear Magnetic Resonance ( 1 H- 15 NHSQC NMR) spectroscopy, validate specific binding at C-terminus, whereas display non-specific interactions along sequence Small-angle neutron scattering (SANS) hydrogen-deuterium exchange mass spectrometry (HDX-MS) further reveal induce distinct changes monomer, leading to more extended structures promoting moderate extension protein. Molecular dynamics simulations (MD) corroborate these findings, showing increase protein’s extension, particularly between non-amyloid beta component (NAC) region bias towards moderately elongated structure. MD, investigate local environment particular solvent effect show water persistence times hydration shell are also increased presence indicating due combination mobility. Atomic force microscopy (AFM) fibrils formed under different ionic conditions polymorphs, suggesting ion-induced biases contribute diversity structures. Collectively, findings underscore pivotal milieu shaping structure thus offering valuable insights molecular underpinnings PD potential therapeutic avenues aimed manipulating dynamics.

Язык: Английский