Alpha-synuclein aggregate (αSyn aggregate) (αSyn aggregate)

Alpha-synuclein is an intrinsically disordered protein primarily localized in presynaptic terminals, where it plays a critical role in synaptic vesicle recycling and neurotransmitter release (UniProt P37840). In synucleinopathies such as Parkinson's disease and Multiple System Atrophy, the protein undergoes a conformational transition from a soluble monomer to toxic oligomers and insoluble amyloid fibrils, which are the principal components of Lewy bodies (PubMed: 30639489). These aggregated species are thought to spread through the brain in a prion-like manner, causing progressive neuronal dysfunction and cell death (PubMed: 29377304). Current drug development focuses on these pathological conformations, utilizing monoclonal antibodies to clear extracellular aggregates and small molecules to inhibit the aggregation process (PubMed: 35105771). The emergence of seed amplification assays has significantly improved the ability to detect these aggregates in clinical settings, facilitating earlier diagnosis and better patient stratification (PubMed: 37059134). Despite these advances, achieving sufficient brain penetration and avoiding interference with the protein's normal physiological functions remain significant hurdles in the development of effective therapies.

Other names

Alpha-synuclein oligomerAlpha-synuclein fibrilLewy body filamentProtofibrilMisfolded alpha-synucleinSNCA aggregate

Therapeutic strategies primarily involve monoclonal antibodies that target extracellular alpha-synuclein to prevent cell-to-cell transmission, small molecules that stabilize the monomeric form or inhibit the nucleation of oligomers, and agents that promote the clearance of existing aggregates through the autophagy-lysosomal pathway (PubMed: 35105771, PubMed: 30639489).