SNCA gene

The SNCA gene (SNCA stands for: Synuclein Alpha) is a protein-coding gene located on chromosome 4q22.1. Alternatively spliced transcripts encoding different isoforms have been identified for this gene. The signaling pathways associated with the SNCA gene include antiviral mechanisms through IFN-stimulated genes and regulation of activated PAK-2p34 through proteasome-mediated degradation. An important paralog of this gene is SNCB.

The protein alpha-synuclein encoded by the SNCA gene belongs to the synuclein family, which also includes beta-synuclein and gamma-synuclein. Synucleins are abundant in the brain. Alpha- and beta-synuclein selectively inhibit phospholipase D2. Synuclein alpha may serve to integrate presynaptic signaling and membrane transport. Defects in the SNCA gene are associated with the development of Parkinson's disease. SNCA peptides are a major component of amyloid plaques in the brains of Alzheimer's patients.

SNCA is a neuronal protein that fulfills multiple functions in synaptic activity, such as the regulation of synaptic vesicle trafficking and the subsequent release of neurotransmitters (Burré J et al. 2010; Logan T et al. 2017). SNCA participates as a monomer in the exocytosis of synaptic vesicles by enhancing vesicle priming, fusion and dilation of exocytotic fusion pores (Logan T et al. 2017; Huang CC et al. 2018). Mechanistically, it acts by increasing local ^Ca2+ release from microdomains, which is essential for enhancing ATP-induced exocytosis (Huang CC et al. 2018).

SNCA also acts as a molecular chaperone in its multimeric membrane-bound state and, in conjunction with cysteine string protein-alpha/DNAJC5, supports the folding of synaptic fusion components, known as SNAREs (Soluble NSF Attachment Protein REceptors), at the presynaptic plasma membrane (Logan T et al. 2017). This chaperone activity is important for the maintenance of normal SNARE complex assembly during the ageing process (Burré J et al. 2010). SNCA also plays a role in the regulation of dopamine neurotransmission by binding to the dopamine transporter (DAT1) and thereby modulating its activity (Butler B et al. 2015).

Diseases associated with SNCA include dementia, Lewy bodies and Parkinson's disease 1, autosomal dominant.

1. Burré J et al. (2010) Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329:1663-1667.
2. Butler B et al. (2015) Dopamine Transporter Activity Is Modulated by α-Synuclein. J Biol Chem 290:29542-29554
3. Huang CC et al. (2018) Soluble α-synuclein facilitates priming and fusion by releasing Ca2+ from the thapsigargin-sensitive Ca2+ pool in PC12 cells. J Cell Sci 131:jcs213017
4. Logan T et al. (2017) α-Synuclein promotes dilation of the exocytotic fusion pore. Nat Neurosci20:681-689