β-Synuclein, crucial for preventing α-synuclein aggregation in healthy neurons, paradoxically forms toxic assemblies at synaptic vesicle at pH 5.8 where neurotransmitters concentrate to millimolar levels. We discovered that neurotransmitter chemical structure dictates β-synuclein aggregation fate at pH 5.8: catecholamines (dopamine, epinephrine, and norepinephrine) potently suppress aggregation while non-catecholamines (acetylcholine, GABA, and serotonin) accelerate polymorphic fibril formation .Epinephrine emerged as the most potent suppressor, achieving >95% aggregation inhibition and complete neuroprotection in SH-SY5Y cells. Surprisingly, biophysical investigation revealed ultra-weak binding (Kd in mM range, confirmed by fluorescence quenching and microscale thermophoresis/MST)—which is much weaker than the conventional drug-target interactions. This “weak-binding paradox” challenges traditional pharmacological paradigms. Time-dependent intervention experiments demonstrated epinephrine’s unique mechanism: it arrests aggregation at any stage—preventing monomer assembly, freezing oligomer maturation, and halting fibril elongation. AFM/TEM imaging confirmed preservation of monomeric β-synuclein, while CD and FTIR spectroscopy showed retention of random-coil structure. We hypothesize that catecholamines undergo auto-oxidation to reactive quinones that covalently modify lysine residues, creating steric blocks to β-sheet formation. Non-catecholamines lack this oxidative pathway, instead promoting hydrophobic collapse through conventional binding. Our findings reveal that catecholaminergic neurons possess intrinsic chemical defense against protein aggregation—protection progressively lost during neurodegeneration when neurotransmitter levels decline. This work establishes that biological potency can arise from chemical reactivity rather than binding affinity, suggesting novel therapeutic strategies for synucleinopathies that could harness covalent chemistry instead of utilizing strong binding interactions. The neurotransmitter-specific effects in this work provide mechanistic insight into selective neuronal vulnerability in Parkinson’s disease.
Hossain et al. (Sun,) studied this question.