A α-synuclein aggregation inhibitor exerts neuroprotective effects via mitochondrial resilience in Parkinson's...

The pathogenesis of Parkinson's disease (PD) is driven by a vicious cycle of α-synuclein (α-Syn) aggregation and mitochondrial collapse. Breaking this pathogenic loop requires disease-modifying therapeutics capable of destabilizing the toxic structural core of α-Syn while simultaneously rescuing bioenergetic failure, highlighting an urgent need for novel dual-action neuroprotective agents.

To identify and characterize A14, a novel small-molecule modulator, and evaluate its dual capacity to inhibit α-Syn fibrillization and mitigate downstream mitochondrial deficits in PD.

Structure-based virtual screening was employed to identify A14 as a targeted inhibitor of the α-Syn fibril β-sheet interface. Its biophysical mechanisms were elucidated using multi-dimensional structural assays. In cellular models and A53T α-Syn transgenic mice, systematically evaluated the therapeutic efficacy, wherein transcriptomics and transmission electron microscopy were adopted to detect mitochondrial integrity, and functional magnetic resonance imaging (fMRI) together with electrophysiology were utilized for the assessment of nigral circuit function.

A14 binds the β-sheet core of α-Syn fibrils with high affinity (Kd = 27.9 ± 2.16 nM), significantly reducing β-sheet content from 21.4% to 9.3% and redirecting the aggregation trajectory into small (< 20 nm), protease-sensitive intermediates. In neuronal models, A14 robustly reduced intracellular α-Syn inclusions via direct biophysical modulation, independent of major proteostasis pathways. In vivo, A14 disrupted the pathological interaction between α-Syn and mitochondria, rescuing cristae ultrastructure, oxidative phosphorylation, and overall bioenergetics. This coordinated restoration of proteostasis and mitochondrial function prevented dopaminergic neuron loss, normalized cortico-basal ganglia-nigral functional connectivity, and significantly ameliorated motor deficits in A53T transgenic mice.

Our findings demonstrate that the A14 engages complementary mechanisms to inhibit α-Syn aggregation and rescue mitochondrial deficits. This dual action stabilizes proteostasis and sustains mitochondrial functionality, nominating A14 as a promising therapeutic candidate for the treatment of PD.