Alpha-synuclein (aggregated) (α-syn) (α-syn)

Alpha-synuclein (SNCA) is a small, 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 [1, 2]. In neurodegenerative conditions known as synucleinopathies, such as Parkinson's disease, Dementia with Lewy bodies, and Multiple system atrophy, the protein undergoes a conformational shift from its soluble monomeric state into toxic oligomers and insoluble beta-sheet-rich fibrils [2, 3, 5]. These aggregated species are the primary constituents of Lewy bodies and are thought to drive neurodegeneration by inducing mitochondrial dysfunction, oxidative stress, and lysosomal impairment [3, 6]. Aggregated alpha-synuclein also exhibits prion-like properties, enabling it to spread between interconnected brain regions and seed the misfolding of native alpha-synuclein in healthy neurons [5, 6]. Therapeutic strategies targeting these aggregates include monoclonal antibodies, such as prasinezumab and cinpanemab, which are designed to bind and clear extracellular aggregates, as well as small molecules like anle138b that aim to inhibit the aggregation process itself [4, 7, 8]. Successfully modulating these pathological species remains a primary goal for developing disease-modifying treatments for Parkinson's and related disorders [7, 10].

Other names

SNCANon-amyloid component of plaque precursor (NACP)PARK1PARK4Alpha-synuclein oligomersAlpha-synuclein fibrilsLewy body protein

Therapeutic agents target aggregated alpha-synuclein to inhibit the transition from soluble monomers to toxic oligomers, promote the clearance of existing fibrils via microglia-mediated phagocytosis, or block the cell-to-cell propagation of pathological seeds [4, 7, 8].