TARGETING α-SYNUCLEIN AGGREGATION FOR PARKINSON'S DISEASE TREATMENT

Parkinson's disease (PD) is a debilitating neurodegenerative disorder for which a cure has yet to be found. A pathological hallmark of PD is intracellular inclusions called Lewy bodies (LBs), which contain insoluble fibrillar aggregates of the protein alpha-synuclein (AS), along with lipids and other proteins in lower concentrations. There is substantial evidence that the progression of PD, and other LB disorders, is linked to the rate at which aberrant aggregates of AS accumulate in the brain, although LBs themselves may not be the pathological culprits. Several strategies are thus being pursued for targeting and modifying the aggregation of AS in the search for future therapies and to enhance our understanding of the causes of PD. This review presents the current evidence for the role of AS in PD and the factors responsible for protein aggregation, and highlights some of the potential therapeutic approaches. One promising approach is the use of small molecules to prevent or otherwise modify the formation of cytotoxic intermediates that form on-pathway to the fibrillar aggregates. Examples of effective inhibitors and methods for their evaluation are given and the prospects for their eventual clinical application are assessed.