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Description

Alpha-synuclein (UniProt: P37840, also known as Non-A beta component of AD amyloid, Non-A4 component of amyloid precursor, NACP) is encoded by the SNCA (also known as NACP, PARK1) gene (Gene ID: 6622) in human. alpha-synuclein is abundantly expressed in the brain and is found in a classic amyloid fibril form within the intra-neuronal Lewy body deposits of Parkinson's disease brains. In its monomeric form it participates in synaptic vesicle exocytosis by enhancing vesicle priming, fusion and dilation of exocytotic fusion pores. It acts by increasing local calcium release from microdomains, which is essential for the enhancement of ATP-induced exocytosis. In its multimeric form it acts as a molecular chaperone assisting in the folding of synaptic fusion components called SNAREs at presynaptic membrane. It is also shown to regulate dopamine release and transport. It reduces neuronal responsiveness to various apoptotic stimuli, leading to a decreased caspase-3 activation. Post-translationally it can be phosphorylated, predominantly on serine residues. Phosphorylation of serine 129 is reported to be selective and extensive in synucleinopathy lesions. In addition, increased phosphorylation of Tyr125, nitration of Tyr39, and glycation of alpha-synuclein have been reported in Parkinsons disease subjects. Nitration of tyrosine residues in alpha-synuclein is observed in the signature inclusions of Parkinsons disease, dementia with Lewy bodies, the Lewy body variant of Alzheimer s disease, and multiple system atrophy brains. EAAC1 -/- mice display age-dependent loss of dopaminergic neurons in the substantia nigra pars compacta and this neuronal loss is accompanied by increased nitrosylated alpha-synuclein and microglial activation. Genetic alterations of SNCA gene are reported to result in aberrant polymerization into fibrils, which is associated with several neurodegenerative diseases (synucleinopathies). (Ref.: Miranda, HV., et al. (2017). Sci. Rep. 7, 13713, Berman, AE., et al. (2011). Ann. Neurol. 69(3), 509 520, Giasson, BI., et al. (2000). Science. 290(5493), 985-989).