O-linked N-acetylglucosamine (O-GlcNAc) is an endogenous form of glycosylation that alters the structure of alpha-synuclein amyloid fibrils and attenuates their pathogenetic properties. The modified fibrils have a significantly reduced ability to seed the aggregation of endogenous alpha-synuclein in cultured neurons and in mice brains in vivo, which results in reduced pathology.