α-Synuclein Fibrils as Penrose Machines: A Chameleon in the Gear

In 1957, Lionel Penrose built the first man-made self-replicating mechanical device and illustrated its function in a series of machine prototypes, prefiguring our current view of the genesis and the proliferation of amyloid fibrils. He invented and demonstrated, with the help of his son Roger, the concepts that decades later, would become the fundamentals of prion and prion-like neurobiology: nucleation, seeding and conformational templating of monomers, linear polymer elongation, fragmentation, and spread. He published his premonitory discovery in a movie he publicly presented at only two conferences in 1958, a movie we thus reproduce here. By making a 30-year-jump in the early 90’s, we evoke the studies performed by Peter Lansbury and his group in which α-Synuclein (α-Syn) was for the first time (i) compared to a prion; (ii) shown to contain a fibrillization-prone domain capable of seeding its own assembly into fibrils; (iii) identified as an intrinsically disordered protein (IDP), and which, in the early 2000s, (iv) was described by one of us as a protein chameleon. We use these temporally distant breakthroughs to propose that the combination of the chameleon nature of α-Syn with the rigid gear of the Penrose machine is sufficient to account for a phenomenon that is of current interest: the emergence and the spread of a variety of α-Syn fibril strains in α-Synucleinopathies.