Inhibitor Development for α-Synuclein Fibril's Disordered Region to Alleviate Parkinson's Disease Pathology

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Amyloid fibrils of alpha-synuclein (α-syn) are central to Parkinson's disease (PD) pathology.
• The C-terminal intrinsically disordered region (IDR) of α-syn fibrils mediates interactions with receptors like LAG3 and RAGE, promoting neuronal spread and inflammation.

Purpose of the Study:

• To identify inhibitors that disrupt α-syn fibril interactions with neuronal receptors.
• To develop novel small molecules targeting the α-syn IDR for therapeutic intervention in PD.

Main Methods:

• High-throughput screening to identify Givinostat (GS) as an α-syn fibril inhibitor.
• Structure-activity relationship studies to optimize GS, leading to compound GSD-16-24.
• Solution-state and solid-state NMR, and cryo-electron microscopy (cryo-EM) to elucidate binding mechanisms.

Main Results:

• GSD-16-24 was identified as a potent inhibitor, binding to the α-syn C-terminal IDR in both monomeric and fibrillar forms.
• GSD-16-24 effectively prevented α-syn fibrils from binding to LAG3 and RAGE receptors.
• The compound significantly reduced α-syn fibril-mediated neuronal propagation and pro-inflammatory responses.

Conclusions:

• Targeting the α-syn C-terminal IDR with small molecules like GSD-16-24 offers a novel therapeutic strategy for Parkinson's disease.
• Disruption of α-syn fibril-receptor interactions can mitigate key pathological processes in PD.
• This approach provides potential leads for developing new clinical drugs to treat Parkinson's disease.