Alpha-synuclein (pathological aggregates) (α-syn)

Alpha-synuclein is a 140-amino acid protein primarily localized in presynaptic terminals of the central nervous system, where it plays a role in synaptic vesicle trafficking and neurotransmitter release (Source: UniProt P37840). In pathological states, the protein undergoes a conformational shift from an intrinsically disordered monomer to toxic oligomers and insoluble fibrillar aggregates, which are the hallmark of synucleinopathies such as Parkinson's disease and Dementia with Lewy bodies (Source: NIH, StatPearls). These aggregates, often found in Lewy bodies and Lewy neurites, exert neurotoxicity by disrupting cellular membranes, impairing mitochondrial function, and overwhelming the proteasomal degradation system. Furthermore, pathological alpha-synuclein exhibits prion-like properties, spreading between neurons and seeding the misfolding of endogenous proteins (Source: PubMed, PMID: 30639489). Therapeutic interventions currently focus on reducing the protein's production, inhibiting its aggregation, or utilizing monoclonal antibodies to clear extracellular species and prevent cell-to-cell transmission (Source: ClinicalTrials.gov). Small molecules like Anle138b aim to stabilize the monomeric form or inhibit the formation of toxic oligomers, while immunotherapies like Prasinezumab target the C-terminus of the protein to facilitate clearance. The development of highly sensitive seed amplification assays has recently revolutionized the ability to detect these pathological aggregates in cerebrospinal fluid and skin biopsies, aiding in patient selection for clinical trials (Source: The Lancet Neurology, 2023).

Other names

SNCANon-amyloid component of plaque precursorNACPLewy body proteinAlpha-synuclein oligomersAlpha-synuclein fibrilsAlpha-synuclein protofibrils

Therapeutic strategies include monoclonal antibodies that bind to and promote the clearance of extracellular aggregates, small molecules that inhibit the misfolding and aggregation of monomers into toxic oligomers, and agents that enhance the autophagic or lysosomal degradation of existing intracellular inclusions (Source: PubMed, PMID: 33571440).