17 Jun 2000

Peter Lansbury, like I and others, has long promulgated the idea that intermediates in CNS disease-related fibrillogenesis processes are likely to be pathogenic, whereas mature matted fibrils (although not desirable) are relatively inert. In a provocative presentation Peter shared new data on the fibrillogenesis and pore forming properties of α-synuclein (α-S). Using AFM he demonstrated that, like Aβ, fibrillogenesis of α-S involves a transient population of oligomeric prefibrillar spheres (primitive protofibrils) and short flexible beaded fibrils (protofibrils, PF) and, under certain circumstances , annular PF.

Protofibrils, like fibrils, are β-sheet-rich structures, whereas monomeric α-S is natively unfolded (random coil). Incubation of monomeric α-S with certain artificial and brain-derived membrane vesicles revealed a weak association of the monomer with the membrane that was accompanied by a partial refolding to produce a helical-rich structure. In contrast, PF were found to bind avidly to membrane vesicles and to retain their strong β signature. Moreover, when PF and membrane vesicles loaded with the Ca2+-sensitive dye Fura 2 were incubated in the presence of extra-vesicular Ca2+, an increase in fluorescence was observed indicating that binding of PF resulted in an increase in membrane permeability to Ca2+.

Interestingly, incubation of primitive PF in the presence of brain-derived membranes produced annular PF which were detected on the vesicular surface by AFM. This observation leads Lansbury to speculate that annular PF act as pores and thus by "non-specifically" increasing membrane permeability lead to a decrease in neuronal viability. While not definitive, the data presented provide a plausible explanation as to how α-S PF may mediate toxicity in PD. Importantly, they explain why neurons with large fibrillar inclusions remain viable, whereas large numbers of neurons die without leaving significant amounts of fibrillar deposits.—Dominic Walsh