Alpha-synuclein (Non-Amyloid-β Component domain) (α-syn NAC)

Alpha-synuclein is a 140-amino acid protein primarily found in neural tissue, where it plays a crucial role in regulating synaptic vesicle trafficking and neurotransmitter release (UniProt P37840). The Non-Amyloid-β Component (NAC) domain, spanning residues 61 to 95, is the highly hydrophobic central region of the protein and is essential for its aggregation into toxic oligomers and amyloid fibrils (PubMed: 25108330). In synucleinopathies such as Parkinson's disease and Dementia with Lewy bodies, the NAC domain undergoes a conformational shift from an intrinsically disordered state to a beta-sheet-rich structure, driving the formation of Lewy bodies (PubMed: 30635028). Because the NAC domain is the primary driver of protein misfolding, it is a major focus for therapeutic intervention. Current drug development strategies include small molecules like Anle138b and peptides designed to bind the NAC region to stabilize the monomeric form or prevent the recruitment of additional proteins into aggregates (PubMed: 23613469). Targeting this domain aims to halt the progression of neurodegeneration by reducing the proteotoxic stress associated with alpha-synuclein accumulation.

Other names

Non-amyloid componentNAC domainSNCA NACNACPNAC regionNon-amyloid-beta component of Alzheimer's disease amyloid

Inhibition of protein aggregation by binding to the hydrophobic NAC domain to prevent the formation of toxic oligomers and amyloid fibrils (PubMed: 25108330).