 Lewy bodies are well-known markers of Parkinson's disease. These inclusions, containing tangled fibrils of alpha-synuclein, are typically found in the postmortem brain tissue of patients with Parkinson's. In fact, alpha-synuclein is generally believed to play a central role in Parkinson's and similar pathologies. In a new study, researchers from the BrainMind Institute at EPFL in Switzerland propose a subtle but critical change to this widely held conception. They provide novel insight into the composition and mechanisms of Lewy body formation and show that the process of Lewy body formation, rather than simply alpha-synuclein fibrillization, is one of the key drivers of neurodegeneration. The team began with a popular system that mimics the formation of salt crystals from preformed seeds. Alpha-synuclein in the cell was induced to form fibrils by first adding a small amount of recombinant alpha-synuclein fibrils. This approach has proven incredibly useful in modeling the formation of alpha-synuclein aggregates linked to neurodegenerative diseases like Parkinson's. But where most studies stop at alpha-synuclein fibrillization, which occurs after about two weeks, the EPFL team stood pat. A few more days of waiting, the early findings hinted would be enough to see fibrils giving way to clumps and ultimately to Lewy body-like structures. They were right, at about three weeks those inclusions began to take shape. But then came the challenge faced by others trying to recreate Lewy bodies in the lab, proving that they are in fact Lewy bodies. For that they turned to the proteomic and transcriptomic analyses. The goal was to test their structures for the biomolecular signatures demonstrated by Lewy bodies gathered from brain tissue. They discovered 15 to 20% proteomic overlap between their homegrown bodies and those found in humans. This may not represent a great overlap, but this is not surprising given that Lewy bodies take months or years to form and mature in human brains. The final test was to link these Lewy bodies to signs of neurodegeneration. Correlative light and electron microscopy revealed a cascade of processes beginning when the Lewy body-like inclusions began to form. Newly formed alpha-synuclein aggregates interacted with mitochondria, sequestering membranous organelles including mitochondria, lysosomes and autophagosomes and proteins during the formation and maturation of the Lewy body-like inclusions and leading to severe mitochondria defects and dysfunction. Further imaging suggests that this mitochondria dysfunction could extend to the synaptic scale, overlapping with reductions in synaptic density and dysregulation of the synaptic transcriptome and ultimately causing cell death. Overall the results agree with recent findings reported on Lewy bodies isolated from Parkinson's disease brains. But where previous research offers snapshots of viral evolution, the team's model allows for the reconstruction of the entire process. This makes the model a powerful platform for elucidating the relationship between fibrillation and neurodegeneration in Parkinson's and other neurodegenerative diseases and for screening for drugs that can block this critical process.