Title : A structure-based strategy to target pathogenic ?-synuclein in Parkinson’s disease
Abstract:
a-Synuclein (aSyn) aggregation is a key factor in neurodegeneration in Parkinson’s disease (PD). We have used the different structural properties of toxic oligomers and amyloid fibrils to identify a family of peptides that bind to these a-synuclein species with low nanomolar affinity without interfering with the monomeric, functional protein. This activity results in high anti-aggregation potency and the ability to prevent oligomer-induced neuronal damage. With a structure-function relationship established, we identified human candidates expressed in the brain with similar binding, anti-aggregation, and detoxifying properties. Administration of the leading candidate in a PD animal model preserved the nigrostriatal pathway and completely prevented motor dysfunction.
Using a combination of structural methods, including cryo-EM, ssNMR, SAXS, XL-MS, and HXD-MS, we have delineated the interaction region between these peptides and a Syn in the context of oligomers. Deletion or mutation of this region abolishes both aSyn aggregation and neurotoxicity, validating it as a disease-relevant structural hotspot. This provided the foundation for generating conformation-specific nanobodies and human IgGs that selectively recognize toxic oligomers and suppress α Syn amyloid formation. Collectively, our findings define a new structure-based therapeutic paradigm for PD, providing both disease-modifying agents and conformation-specific tools with strong potential for diagnosis and intervention in synucleinopathies.
