Alpha-synuclein (SNCA) aggregates (SNCA)

Alpha-synuclein (SNCA) is a 140-amino acid protein predominantly localized in presynaptic terminals of the central nervous system (UniProt P37840). While its physiological role involves regulating synaptic vesicle trafficking and neurotransmitter release, its pathological aggregation is the defining feature of synucleinopathies, including Parkinson's disease and Multiple System Atrophy (PubMed: 31582155). In these conditions, SNCA transitions from a soluble monomer to toxic oligomers and insoluble amyloid-like fibrils, which are the primary components of Lewy bodies (NIH: StatPearls - Parkinson Disease). These aggregates disrupt proteasomal and lysosomal clearance, induce mitochondrial dysfunction, and promote neuroinflammation (PubMed: 30612212). The aggregation process is thought to occur in a prion-like manner, where misfolded proteins seed the aggregation of healthy monomers in adjacent neurons (PubMed: 29377314). Therapeutic interventions currently in clinical development, such as the monoclonal antibody Prasinezumab, aim to bind and clear extracellular SNCA aggregates to prevent their spread (ClinicalTrials.gov: NCT03100149). Other approaches include small molecules like Anle138b that inhibit the formation of toxic oligomers or antisense oligonucleotides that reduce total SNCA expression (PubMed: 23612469). Targeting SNCA aggregates is considered a disease-modifying strategy, as it addresses the underlying proteinopathy rather than just providing symptomatic relief (PubMed: 32071438).

Other names

Alpha-synuclein fibrilsLewy body proteinNACPPARK1PARK4Non-amyloid beta component of AD amyloid

Inhibition of protein aggregation, promotion of aggregate clearance via immunotherapy, stabilization of monomeric alpha-synuclein, and reduction of alpha-synuclein expression.