Alpha-synuclein (aSyn) is a protein that in humans is encoded by the SNCA gene. It is a neuronal protein involved in the regulation of synaptic vesicle trafficking and the release of neurotransmitters.

Alpha-synuclein is abundant in the brain, with smaller amounts present in the heart, muscles, and other tissues. Within the brain, it is primarily localized to the axon terminals of presynaptic neurons. There, it interacts with phospholipids and other proteins. Presynaptic terminals release neurotransmitters from specialized compartments called synaptic vesicles, a process essential for neuronal communication and normal brain function.

In Parkinson's disease and related synucleinopathies, abnormal, insoluble forms of alpha-synuclein accumulate within neurons as inclusions known as Lewy bodies. Mutations in the SNCA gene are linked to familial forms of Parkinson's disease. During the process of seeded nucleation, alpha-synuclein adopts a cross-beta sheet structure characteristic of amyloid fibrils.

The human alpha-synuclein protein consists of 140 amino acids. A fragment of alpha-synuclein, known as the non-amyloid beta component (NAC) of Alzheimer's disease amyloid, was initially isolated from an amyloid-rich brain fraction and shown to derive from a precursor protein named NACP. NACP was subsequently identified as the human homologue of synuclein from the electric ray genus Torpedo, leading to its renaming as human alpha-synuclein.

Alpha-synuclein is a synuclein protein primarily found in neural tissue, making up as much as one percent of all proteins in the cytosol of brain cells. It is expressed highly in neurons within the frontal cortex, hippocampus, striatum, and olfactory bulb, but can also be found in the non-neuronal glial cells.

It has been established that alpha-synuclein is extensively localized in the nucleus of mammalian brain neurons, suggesting a role of alpha-synuclein in the nucleus. Synuclein is however found predominantly in the presynaptic termini, in both free or membrane-bound forms, with roughly 15% of synuclein being membrane-bound at any moment in neurons.

It has also been shown that alpha-synuclein is localized in neuronal mitochondria. Alpha-synuclein is highly expressed in the mitochondria in olfactory bulb, hippocampus, striatum and thalamus, where the cytosolic alpha-synuclein is also rich. However, the cerebral cortex and cerebellum are two exceptions, which contain rich cytosolic alpha-synuclein but very low levels of mitochondrial alpha-synuclein. It has been shown that alpha-synuclein is localized in the inner membrane of mitochondria, and that the inhibitory effect of alpha-synuclein on complex I activity of the mitochondrial respiratory chain is dose-dependent. Thus, it is suggested that alpha-synuclein in mitochondria is differentially expressed in different brain regions and the background levels of mitochondrial alpha-synuclein may be a potential factor affecting mitochondrial function and predisposing some neurons to degeneration.

At least three isoforms of synuclein are produced through alternative splicing. The majority form of the protein, and the one most investigated, is the full-length protein of 140 amino acids. Other isoforms are alpha-synuclein-126, which lacks residues 41-54 due to loss of exon 3; and alpha-synuclein-112, which lacks residues 103-130 due to loss of exon 5.