Alpha-synuclein (α-syn) (α-syn)

Alpha-synuclein is a 140-amino acid protein primarily localized in the presynaptic terminals of neurons, where it plays a role in synaptic vesicle trafficking and neurotransmitter release (UniProt P37840). In neurodegenerative disorders known as synucleinopathies, the protein undergoes a conformational change from its native soluble state into toxic oligomers and eventually forms insoluble amyloid fibrils that aggregate into Lewy bodies and Lewy neurites (PubMed: 30655352). These misfolded species are thought to exert neurotoxicity through proteasomal dysfunction, mitochondrial impairment, and the induction of neuroinflammation (PubMed: 29377304). Therapeutic strategies targeting toxic alpha-synuclein focus on preventing its aggregation, promoting the clearance of existing aggregates via immunotherapy, or reducing its overall expression (PubMed: 35931810). Successful modulation of this target is considered a potential disease-modifying approach for Parkinson's disease and related dementias, with several candidates currently in clinical trials (PubMed: 34138063). Monitoring target engagement and disease progression often involves advanced seed amplification assays in cerebrospinal fluid or skin biopsies to detect misfolded protein templates (PubMed: 37059153).

Other names

SNCANon-amyloid component of plaque precursorNACPPARK1PARK4Alpha-synuclein aggregatesMisfolded alpha-synucleinOligomeric alpha-synuclein

Passive immunization using monoclonal antibodies to clear extracellular aggregates, small molecule inhibition of protein aggregation and oligomerization, stabilization of the physiological monomeric state, and reduction of total protein levels via antisense oligonucleotides or translational inhibitors.