Alpha-synuclein toxic aggregates (α-syn aggregates)

Alpha-synuclein is a 140-amino acid protein primarily localized in the presynaptic terminals of neurons, where it plays a crucial role in regulating synaptic vesicle trafficking and neurotransmitter release (UniProt P37840). Under pathological conditions, this intrinsically disordered protein undergoes a conformational shift, leading to the formation of toxic oligomers and insoluble amyloid fibrils, which are the primary components of Lewy bodies (PubMed: 31582855). These toxic aggregates are central to the pathogenesis of synucleinopathies, including Parkinson's disease, Dementia with Lewy bodies, and Multiple System Atrophy, where they cause neuronal dysfunction and death (PubMed: 30612234). The aggregates are believed to spread through the brain in a prion-like manner, facilitating the progression of neurodegeneration (PubMed: 23613471). Therapeutic strategies currently under development focus on reducing the levels of these toxic species through monoclonal antibodies, such as Prasinezumab, or small molecules like Anle138b that inhibit aggregation (Nature Reviews Drug Discovery, 2022). By targeting the toxic aggregate specifically, researchers aim to preserve the functional monomeric form of the protein while halting the disease's progression.

Other names

Alpha-synuclein oligomersAlpha-synuclein fibrilsLewy body filamentsProtofibrilsMisfolded alpha-synucleinSNCA aggregatesPathological alpha-synuclein

Therapeutic strategies include monoclonal antibodies that bind and neutralize extracellular aggregates to prevent spreading, small molecules that inhibit the misfolding and aggregation of monomers, and agents that enhance the clearance of existing fibrils via the autophagy-lysosome pathway.