Open AccessComparison of N-Acetyl-Glucosamine to Other Monosaccharides Reveals Structural Differences for the Inhibition of α-Synuclein Aggregation
Author(s) -
Ana Galesic,
Ananya Rakshit,
Giuliano Cutolo,
Ricardo Palos Pacheco,
Aaron T. Balana,
Stuart P. Moon,
Matthew R. Pratt
Publication year - 2021
Publication title -
acs chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.899
H-Index - 111
eISSN - 1554-8937
pISSN - 1554-8929
DOI - 10.1021/acschembio.0c00716
Subject(s) - monosaccharide , amyloid (mycology) , chemistry , mannose , biochemistry , galactosamine , glycosylation , glucosamine , intracellular , inorganic chemistry
O -GlcNAc modification of the microtubule associated protein tau and α-synuclein can directly inhibit the formation of the associated amyloid fibers associated with major classes of neurodegenerative diseases. However, the mechanism(s) by which this posttranslational modification (PTM) inhibit amyloid aggregation are still murky. One hypothesis is that O -GlcNAc simply acts as a polyhydroxylated steric impediment to the formation of amyloid oligomers and fibers. Here, we begin to test this hypothesis by comparing the effects of O -GlcNAc to other similar monosaccharides-glucose, N -acetyl-galactosamine (GalNAc), or mannose-on α-synuclein amyloid formation. Interestingly, we find that this quite reasonable hypothesis is not entirely correct. More specifically, we used four types of biochemical and biophysical assays to discover that the different sugars display different effects on the inhibition of amyloid formation, despite only small differences between the structures of the monosaccharides. These results further support a more detailed investigation into the mechanism of amyloid inhibition by O -GlcNAc and has potential implications for the evolution of N -acetyl-glucosamine as the monosaccharide of choice for widespread intracellular glycosylation.