Phosphorylation and O-GlcNAcylation at the same α-synuclein site generate distinct fibril structures

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Alpha-synuclein amyloid fibrils are key to Parkinson's disease pathogenesis.
• Posttranslational modifications influence alpha-synuclein conformation, aggregation, and function.

Purpose of the Study:

• To investigate the impact of phosphorylation and O-GlcNAcylation at the same site (S87) on alpha-synuclein fibril structure and neuropathology.
• To understand how these modifications alter fibril formation and disease-related activity.

Main Methods:

• Semi-synthesis of site-specifically modified alpha-synuclein monomers (pS87 and gS87).
• Cryo-electron microscopy (Cryo-EM) for structural determination of fibrils.
• Assessment of neurotoxicity and propagation activity of modified fibrils.

Main Results:

• Phosphorylated (pS87) and O-GlcNAcylated (gS87) alpha-synuclein form distinct fibril structures.
• gS87 fibrils adopt an iron-like fold, while pS87 fibrils form an arch-like structure due to C-terminal region repulsion.
• Both pS87 and gS87 fibrils exhibit reduced neurotoxicity and propagation compared to unmodified fibrils.

Conclusions:

• Different posttranslational modifications at the same residue can yield unique amyloid fibril architectures.
• This highlights a direct link between specific posttranslational modifications and the resulting fibril structure and associated pathology.
• Understanding these structure-function relationships is crucial for developing Parkinson's disease therapeutics.