Parkinson's disease-associated alpha-sylnuclein is more fibrillogenic thanbeta- and gamma-synuclein and cannot cross-seed its homologs

Parkinson's disease (PD) is a neurodegenerative disorder that is pathologic ally characterized by the presence of intracytoplasmic Lewy bodies. Recentl y, 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 homolog ous genes beta- and gamma -synuclein. alpha -Synuclein forms the major fibr illar component of Lewy bodies, but these do not stain for beta- or gamma - synuclein. This result is very surprising, given the extent of sequence con servation and the high similarity in expression and subcellular localizatio n, in particular between alpha- and beta -synuclein, Here we compare in vit ro fibrillogenesis of all three purified synucleins, We show that fresh sol utions of alpha-, beta-, and gamma- synuclein show the same natively unfold ed structure. While over time alpha -synuclein forms the previously describ ed fibrils, no fibrils could be defected for beta- and gamma -synuclein und er the same conditions. Most importantly, beta- and gamma -synuclein could not be cross-seeded with alpha -synuclein fibrils. How ever, under conditio ns that drastically accelerate aggregation, gamma -synuclein can form fibri ls with a lag phase roughly three times longer than alpha -synuclein. These results indicate that beta- and gamma -synuclein are intrinsically less fi brillogenic than alpha -synuclein and cannot form mixed fibrils with alpha -synuclein, which mag explain why they do not appear in the pathological ha llmarks of PD, although they are closely related to alpha -synuclein and ar e also abundant in brain.