Alpha-synuclein aggregate (α-syn) (α-syn)

Alpha-synuclein is a 140-amino acid protein primarily localized in the presynaptic terminals of neurons, where it plays a critical role in regulating synaptic vesicle trafficking and neurotransmitter release [UniProt P37840]. Under pathological conditions, the protein undergoes a conformational shift from its native, intrinsically disordered state into toxic oligomers and insoluble amyloid fibrils [PubMed: 30612035]. These aggregated forms are the hallmark of synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, where they accumulate as Lewy bodies and Lewy neurites [NIH: PMC7068635]. The aggregation process is thought to follow a prion-like mechanism, where misfolded seeds induce the misfolding of healthy monomers and spread throughout the central nervous system [Nature: 10.1038/s41582-022-00641-4]. Therapeutic strategies targeting aggregated alpha-synuclein include monoclonal antibodies designed to bind and clear extracellular aggregates, thereby halting disease progression [PubMed: 33434123]. Small molecule inhibitors are also being investigated for their ability to stabilize the monomeric form or disrupt the formation of toxic beta-sheet structures [ClinicalTrials.gov: NCT04450888]. Monitoring the efficacy of these treatments often involves advanced biomarkers such as the alpha-synuclein seed amplification assay (αSyn-SAA), which detects minute amounts of misfolded protein in cerebrospinal fluid [Lancet Neurology: 10.1016/S1474-4422(23)00109-6]. Despite the promise of these therapies, challenges remain regarding blood-brain barrier penetration and the potential for off-target effects on the protein's physiological functions [PubMed: 31203787].

Other names

Alpha-synuclein fibrilsOligomeric alpha-synucleinSNCA aggregatesLewy body proteinNon-amyloid component (NAC) of Alzheimer's disease amyloidAlpha-synuclein filaments

Monoclonal antibodies target extracellular alpha-synuclein aggregates to promote microglial-mediated clearance and block cell-to-cell propagation, while small molecules inhibit the aggregation of monomers into toxic oligomers or fibrils and stabilize the native protein conformation.