Reverse engineering Lewy bodies: how far have we come and how far can we go?

Lewy bodies (LBs) are alpha-synuclein (alpha-syn)-rich intracellular inclusions that are an important pathological hallmark of Parkinson disease and several other neurodegenerative diseases. Increasing evidence suggests that the aggregation of alpha-syn has a central role in LB formation and is one of the key processes that drive neurodegeneration and pathology progression in Parkinson disease. However, little is known about the mechanisms underlying the formation of LBs, their biochemical composition and ultrastructural properties, how they evolve and spread with disease progression, and their role in neurodegeneration. In this Review, we discuss current knowledge of alpha-syn pathology, including the biochemical, structural and morphological features of LBs observed in different brain regions. We also review the most used cellular and animal models of alpha-syn aggregation and pathology spreading in relation to the extent to which they reproduce key features of authentic LBs. Finally, we provide important insights into molecular and cellular determinants of LB formation and spreading, and highlight the critical need for more detailed and systematic characterization of alpha-syn pathology, at both the biochemical and structural levels. This would advance our understanding of Parkinson disease and other neurodegenerative diseases and allow the development of more-reliable disease models and novel effective therapeutic strategies.

Automated summary

Lewy bodies (LBs) are important pathological features of Parkinson disease and other neurodegenerative diseases, with increasing evidence suggesting that the aggregation of alpha-synuclein plays a central role in LB formation. However, little is known about the mechanisms underlying LB formation, their biochemical and ultrastructural properties, evolution and spreading with disease progression, and their role in neurodegeneration.