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


No Available Comments

Make a Comment

To make a comment you must login or register.


No Available References

Further Reading

No Available Further Reading