Alpha-synuclein non-amyloid-beta component core (NACore) (NACore)

The alpha-synuclein non-amyloid-beta component core (NACore) refers to the highly amyloidogenic segment of the alpha-synuclein protein, specifically encompassing residues 68-78 (GAVVTGVTAVA). This region is essential for the protein's transition from a soluble, intrinsically disordered monomer into insoluble cross-beta sheet fibrils, which are the primary constituents of Lewy bodies in Parkinson's disease (Rodriguez et al., Nature 2015, PMID: 26352473). Under normal physiological conditions, alpha-synuclein is localized at presynaptic terminals where it interacts with lipid membranes to regulate synaptic vesicle trafficking and neurotransmitter release (UniProt P37840). However, the NACore region's high hydrophobicity drives the nucleation and propagation of toxic aggregates in synucleinopathies. Therapeutic strategies targeting the NACore aim to prevent misfolding or disrupt existing aggregates using small molecules like Anle138b or UCB0599, which are designed to stabilize the native state or promote clearance (ClinicalTrials.gov). Because the NACore is the structural heart of the pathogenic fibril, it serves as a high-priority target for structure-based drug design and the development of diagnostic seed amplification assays.

Other names

NAC regionNon-amyloid-beta component of Alzheimer's disease amyloidSNCA(68-78)Amyloidogenic core of alpha-synucleinAlpha-synuclein (68-78)

Inhibition of protein aggregation and fibril formation by binding to the hydrophobic NACore region to sterically hinder beta-sheet stacking and stabilize non-toxic monomeric or off-pathway species.