Alpha-synuclein (N-terminal region, misfolded species) (α-Syn)

Alpha-synuclein is a 140-amino acid protein primarily localized in presynaptic terminals, where it plays a crucial role in regulating synaptic vesicle trafficking and neurotransmitter release (UniProt: P37840). In neurodegenerative disorders known as synucleinopathies, such as Parkinson's disease and Dementia with Lewy bodies, the protein undergoes a conformational change from its native state into toxic, misfolded oligomers and insoluble fibrils (PubMed: 31034788). The N-terminal region (residues 1-60) is highly conserved and contains amphipathic alpha-helical motifs that mediate membrane binding; however, it also plays a critical role in the initiation of protein aggregation (PubMed: 28439104). Therapeutic strategies targeting the N-terminal region of pathologic alpha-synuclein species aim to neutralize toxic aggregates, prevent cell-to-cell propagation (seeding), and enhance the clearance of proteopathic strains (PubMed: 32103031). Monoclonal antibodies like cinpanemab have been designed to specifically recognize these N-terminal epitopes to mitigate neurodegeneration while potentially sparing the physiological function of the monomeric protein (ClinicalTrials.gov: NCT03318523). Recent advancements in diagnostic techniques, such as the alpha-synuclein seed amplification assay, allow for the detection of these pathologic species in cerebrospinal fluid with high sensitivity (Lancet Neurology: 2023, 22(5):399-411).

Other names

SNCANACPPARK1PARK4Non-amyloid component of plaque precursor

Passive immunization targeting the N-terminal region of aggregated alpha-synuclein to prevent cell-to-cell propagation and promote clearance.