Parkinson's disease-associated α-sylnuclein is more fibrillogenic than β- and γ-synuclein and cannot cross-seed its homologs

Parkinson's disease (PD) is a neurodegenerative disorder that is pathologically characterized by the presence of intracytoplasmic Lewy bodies. Recently, two point mutations in alpha -synuclein were found to be associated with familial PD, but as of yet no mutations have been described in the homologous genes beta- and gamma -synuclein. alpha -Synuclein forms the major fibrillar component of Lewy bodies, but these do not stain for beta- or gamma -synuclein. This result is very surprising, given the extent of sequence conservation and the high similarity in expression and subcellular localization, in particular between alpha- and beta -synuclein, Here we compare in vitro fibrillogenesis of all three purified synucleins, We show that fresh solutions of alpha-, beta-, and gamma- synuclein show the same natively unfolded structure. While over time alpha -synuclein forms the previously described fibrils, no fibrils could be defected for beta- and gamma -synuclein under the same conditions. Most importantly, beta- and gamma -synuclein could not be cross-seeded with alpha -synuclein fibrils. How ever, under conditions that drastically accelerate aggregation, gamma -synuclein can form fibrils with a lag phase roughly three times longer than alpha -synuclein. These results indicate that beta- and gamma -synuclein are intrinsically less fibrillogenic than alpha -synuclein and cannot form mixed fibrils with alpha -synuclein, which mag explain why they do not appear in the pathological hallmarks of PD, although they are closely related to alpha -synuclein and are also abundant in brain.