Triprolidine Interferes with α-Synuclein Fibrillation and Remodels Aggregate Structure via Conformational Modulation.
Triprolidine Interferes with α-Synuclein Fibrillation and Remodels Aggregate Structure via Conformational Modulation.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Alīgarh, IN · Author affiliation
Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, UP202002, India.Location evidence
FR · Author affiliation · country only
Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, PSL University, INSERM, CNRS, Paris75005, France.Location evidence
Tampa, US · Author affiliation
Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida33612, United States.Location evidence
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Original abstract
Parkinson's disease (PD) is characterized by the pathological aggregation of α-synuclein (α-syn) into β-sheet-rich fibrils, contributing to neuronal toxicity and oxidative stress. In this study, we investigated the inhibitory and disaggregating effects of Triprolidine (TC) on α-syn fibrillation through a combined experimental and computational approach. Biophysical assays, including ThT assay, DLS, and ANS assays, demonstrated that TC inhibits α-syn fibrillation in a concentration-dependent manner (IC50 ≈ 255 μM), disrupts preformed fibrils, and maintains the protein's native form. CD data further revealed that TC prevents the transition of α-syn to its toxic β-sheet-rich form and facilitates partial structural reversal during disaggregation. To elucidate the molecular mechanism of inhibition, we performed all-atom molecular dynamics (MD) simulations followed by Markov State Model (MSM) construction. The simulations revealed that TC binding remodels the conformational landscape of α-syn by stabilizing compact, disordered states and reducing the population of β-sheet-prone intermediates, particularly in the aggregation-prone NAC region. MSM analysis identified metastable states with diminished aggregation potential and reduced inter-residue contact probability, offering mechanistic insights into how TC interferes with early nucleation events. TC attenuates seeded fibrillation in a concentration-dependent manner too. Complementary cellular assays, including MTT and hemolytic assays, confirmed a significant reduction in α-syn-induced cytotoxicity upon TC treatment, with a decrease in ROS levels as confirmed by the DCFH-DA assay. Together, these findings demonstrate that TC modulates both the structural dynamics and functional toxicity of α-synuclein, and highlight its potential as a promising chemical modulator for further investigation in PD-related protein aggregation.