From Glycation to Toxicity: α-Synuclein Oligomers, Oxidative Stress, and Multi-Targeted Protection by Trans-Ferulic Acid.

Glycation, a spontaneous reaction between sugars and biomolecules, is a central driver of oxidative stress and protein dysfunction in metabolic and neurodegenerative disorders. α-Synuclein (α-Syn), a key protein implicated in Parkinson's disease, is particularly susceptible to modification by reactive carbonyl species such as methylglyoxal (Me) due to its lysine-rich structure. These modifications result in the formation of advanced glycation end products (AGEs), which promote protein aggregation, impair cellular clearance, and induce oxidative and inflammatory damage via the AGE-RAGE axis. This cascade, characterised by increased reactive oxygen and nitrogen species, mitochondrial dysfunction, and metabolic imbalance, accelerates neuronal degeneration and disease progression.This study investigates trans-ferulic acid (TF) as a multifunctional therapeutic candidate targeting this interconnected network. TF effectively inhibited glycation in both ribose and Me-induced α-Syn systems, demonstrating strong antiglycation potential. Additionally, TF exhibited significant scavenging activity against hydrogen peroxide and nitric oxide, underscoring its capacity to reduce oxidative and nitrosative stress. TF also inhibited α-glucosidase, indicating a further mechanism for controlling glucose availability and limiting the formation of reactive intermediates. Collectively, these findings identify TF as a promising multi-target agent capable of disrupting the glycation-oxidative stress cycle at multiple levels. By concurrently reducing reactive species, suppressing carbonyl formation, and limiting protein aggregation, TF represents a compelling strategy to mitigate glycation-driven toxicity and its pathological consequences.