Alpha-synuclein

1XQ8, 2JN5, 2KKW, 2M55, 2X6M, 3Q25, 3Q26, 3Q27, 3Q28, 3Q29, 4BXL, 4R0U, 4R0W, 4RIK, 4RIL, 4ZNN, 5CRW, 2N0A662220617ENSG00000145335ENSMUSG00000025889P37840O55042NM_000345NM_001146054NM_001146055NM_007308NM_001042451NM_009221NP_000336NP_001139526NP_001139527NP_009292NP_001035916NP_033247Alpha-synuclein is a protein that, in humans, is encoded by the SNCA gene. It is abundant in the brain while smaller amounts are found in the heart, muscle, and other tissues. In the brain, alpha-synuclein is found mainly at the tips of nerve cells (neurons) in specialized structures called presynaptic terminals. Within these structures, alpha-synuclein interacts with phospholipids and proteins. Presynaptic terminals release chemical messengers, called neurotransmitters, from compartments known as synaptic vesicles. The release of neurotransmitters relays signals between neurons and is critical for normal brain function.1xq8: Human micelle-bound alpha-synuclein Alpha-synuclein is a protein that, in humans, is encoded by the SNCA gene. It is abundant in the brain while smaller amounts are found in the heart, muscle, and other tissues. In the brain, alpha-synuclein is found mainly at the tips of nerve cells (neurons) in specialized structures called presynaptic terminals. Within these structures, alpha-synuclein interacts with phospholipids and proteins. Presynaptic terminals release chemical messengers, called neurotransmitters, from compartments known as synaptic vesicles. The release of neurotransmitters relays signals between neurons and is critical for normal brain function. Although the function of alpha-synuclein is not well understood, studies suggest that it plays a role in restricting the mobility of synaptic vesicles, consequently attenuating synaptic vesicle recycling and neurotransmitter release. An alternate view is that alpha-synuclein binds to VAMP2 (a synaptobrevin) and stabilizes SNARE complexes; though recent studies indicate that alpha-synuclein/VAMP2 binding is critical for alpha-synuclein mediated attenuation of synaptic vesicle recycling, connecting the two seemingly divergent views. It may also help regulate the release of dopamine, a type of neurotransmitter that is critical for controlling the start and stop of voluntary and involuntary movements. The human alpha-synuclein protein is made of 140 amino acids and is encoded by the SNCA gene. An alpha-synuclein fragment, known as the non-Abeta component (NAC) of Alzheimer's disease amyloid, originally found in an amyloid-enriched fraction, was shown to be a fragment of its precursor protein, NACP. It was later determined that NACP was the human homologue of Torpedo synuclein. Therefore, NACP is now referred to as human alpha-synuclein. Alpha-synuclein is a synuclein protein of unknown function primarily found in neural tissue, making up as much as 1% of all proteins in the cytosol of brain cells. It is predominantly expressed in the neocortex, hippocampus, substantia nigra, thalamus, and cerebellum. It is predominantly a neuronal protein, but can also be found in the neuroglial cells. In melanocytic cells, SNCA protein expression may be regulated by MITF. 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 in 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 aretwo 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 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 residue 103-130 due to loss of exon 5. Alpha-synuclein in solution is considered to be an intrinsically disordered protein, i.e. it lacks a single stable 3D structure. As of 2014, an increasing number of reports suggest, however, the presence of partial structures or mostly structured oligomeric states in the solution structure of alpha-synuclein even in the absence of lipids. This trend is also supported by a large number of single molecule (optical tweezers) measurements on single copies of monomeric alpha-synuclein as well as covalently enforced dimers or tetramers of alpha-synuclein. Alpha-synuclein is specifically upregulated in a discrete population of presynaptic terminals of the brain during a period of acquisition-related synaptic rearrangement.It has been shown that alpha-synuclein significantly interacts with tubulin, and that alpha-synuclein may have activity as a potential microtubule-associated protein, like tau.