Understanding the transformation of soluble α-synuclein into pathological Lewy bodies has been a long-standing challenge, with great scientific and clinical importance. Mechanisms proposed in the past, obtained from experiments in which cells and animals were exposed to pre-formed fibrils of α-synuclein, rarely capture the disease onset in humans, failing to reproduce the initial formation of Lewy bodies. In this seminar, I will discuss our latest data indicating that α- synuclein drives condensation-based inclusions that sequester organelles, recapitulating key features of patient Lewy bodies — without fibril seeding. We employ in vitro reconstitutions, modeling and a minimal in cellulo system to recapitulate the formation of Lewy body-like structures (LBLs). By combining live- cell imaging and soft X-ray tomography, we found that LBLs can sequester membrane-bound organelles, resulting in the mitochondria accumulation at the interface of LBLs in the actin-dependent manner. Furthermore, these LBLs represent a hub for the formation of α-synuclein fibrils. Together, our findings establish a mechanistic framework for early Lewy body biogenesis and highlight condensate biology as a promising therapeutic target in synucleinopathies.
Keywords: α-synuclein, Lewy bodies, live- cell imaging, mitochondria, tomography
This part of the website could either be in French or English, depending on the sources of the actualities.