Natural Bioactives Targeting α- Synuclein Aggregation in PD: A Review of Multi-mechanism Phytochemicals

Parkinson's Disease (PD) is a progressive neurodegenerative disorder characterised by the misfolding and aggregation of α-synuclein, a central pathological event that contributes to oxidative stress, mitochondrial dysfunction, impaired proteostasis, neuroinflammation, synaptic dysfunction and progressive dopaminergic neuronal loss. This review highlights current research on natural bioactive compounds that target α-synuclein aggregation as potential disease-modifying therapies for PD. Relevant material was identified through searches of major scientific databases, including PubMed, Google Scholar, Scopus and Web of Science, focused on research studying natural products and α-synuclein-associated neurodegeneration. The review examines significant types of phytochemicals, including flavonoids, polyphenols, alkaloids, terpenoids, and related natural substances such as baicalein, Epigallocatechin-3-Gallate (EGCG), berberine, curcumin, naringenin, mangiferin, silibinin, and oleuropein etc. Together, these substances have shown a variety of neuroprotective mechanisms in preclinical models such as preventing α-synuclein fibrillization, improving protein clearance pathways, reducing oxidative stress and neuroinflammation, maintaining mitochondrial function, and modifying cellular signalling pathways related to neuronal survival. Important translational obstacles are also highlighted by the current data, such as low oral bioavailability, quick metabolic breakdown, inadequate brain exposure, and the lack of clinical efficacy for several prospective candidates. Most of the information currently available comes from preclinical trials, even though natural bioactive substances constitute a potential avenue of investigation for targeting α- synuclein disease. To determine their therapeutic potential as disease-modifying therapies, more drug-delivery optimisation, pharmacokinetic characteristics, and well-planned clinical studies would be necessary for Parkinson's disease.