α-Synuclein in Lewy Body Diseases: Progress, Remaining Challenges and Future Perspectives

Lewy bodies (LBs) are the main pathological feature of the neurodegenerative diseases Parkinson's disease and Dementia with LBs. Since their discovery over 100 years ago, it is only in the last three decades, that, a wealth of genetic, pathological and pre-clinical evidence puts the spotlight on accumulated α-Synuclein (α-Syn) as the main component of LBs and implicated as a driver of these diseases. This has catapulted clinical trials for these diseases focussing on strategies to remove, reduce, disaggregate and prevent propagation of α-Syn. Advances in technical approaches have started to build a bigger picture of the complexity of LBs extending beyond α-Syn. There is still much to be learned about the processes underlying the formation and structure of LBs and their relationship to neurodegeneration. This will likely impact upon how we target these diseases therapeutically, diagnose them and build clinical trials. Here, we will discuss LBs in the context of α-Syn and other features, modelling strategies and how to direct research moving forwards in order to get clinical results. A more complete understanding of LBs and potential novel targets that drive their formation will likely lead to better outcomes in LB diseases.