alpha-synuclein alpha-synuclein alpha-synuclein (asyn) is a protein that, in humans, is encoded by the snca gene. alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release. sncaavailable structurespdbortholog search: pdbe rcsb list of pdb id codes1xq8, 2jn5, 2kkw, 2m55, 2x6m, 3q25, 3q26, 3q27, 3q28, 3q29, 4bxl, 4r0u, 4r0w, 4rik, 4ril, 4znn, 5crw, 2n0aidentifiersaliasessnca, nacp, park1, park4, pd1, synuclein alphaexternal idsomim: 163890 mgi: 1277151 homologene: 293 genecards: snca gene location (human)chr.chromosome 4 (human)band4q22.1start89,700,345 bpend89,838,315 bpgene location (mouse)chr.chromosome 6 (mouse)band6 b3|6 29.15 cmstart60,708,559 bpend60,806,839 bprna expression patternbgeehumanmouse (ortholog)top expressed incancellous boneorbitofrontal cortexponsbrodmann area 46endothelial cellbrodmann area 23postcentral gyrusmiddle temporal gyrusmonocytebrodmann area 9top expressed insubiculumnucleus accumbensbarrel cortexventral tegmental areahippocampus properhabenulaprefrontal cortexolfactory epitheliumregion i of hippocampus properolfactory tuberclemore reference expression databiogpsmore reference expression datagene ontologymolecular function calcium ion binding protein n-terminus binding ferrous iron binding phospholipid binding metal ion binding fatty acid binding oxidoreductase activity magnesium ion binding histone binding zinc ion binding cysteine-type endopeptidase inhibitor activity involved in apoptotic process protein binding kinesin binding tau protein binding copper ion binding microtubule binding alpha-tubulin binding phosphoprotein binding phospholipase d inhibitor activity beta-tubulin binding identical protein binding dynein complex binding hsp70 protein binding cuprous ion binding enzyme binding protein domain specific binding phospholipase binding actin binding snare binding cellular component postsynapse cytoplasm cytosol membrane synapse extracellular region mitochondrion actin cytoskeleton perinuclear region of cytoplasm cytoskeleton nucleus rough endoplasmic reticulum ribosome synaptic vesicle mitochondrial respiratory chain complex i platelet alpha granule membrane terminal bouton lysosome golgi apparatus intracellular membrane-bounded organelle growth cone plasma membrane axon cell cortex inclusion body nuclear outer membrane axon terminus cell junction cytoplasmic vesicle membrane extracellular space supramolecular fiber neuronal cell body mitochondrial outer membrane mitochondrial inner membrane mitochondrial intermembrane space mitochondrial matrix presynapse synaptic vesicle membrane biological process negative regulation of neuron apoptotic process negative regulation of norepinephrine uptake response to interleukin-1 response to interferon-gamma regulation of glutamate secretion response to magnesium ion synaptic transmission, dopaminergic regulation of reactive oxygen species biosynthetic process positive regulation of protein serine/threonine kinase activity cellular response to epinephrine stimulus positive regulation of synaptic transmission cellular response to copper ion regulation of synaptic vesicle recycling activation of cysteine-type endopeptidase activity involved in apoptotic process response to cocaine positive regulation of glutathione peroxidase activity negative regulation of platelet-derived growth factor receptor signaling pathway negative regulation of serotonin uptake regulation of dopamine secretion regulation of long-term neuronal synaptic plasticity response to iron(ii) ion behavioral response to cocaine regulation of locomotion adult locomotory behavior positive regulation of neurotransmitter secretion cellular response to fibroblast growth factor stimulus positive regulation of peptidyl-serine phosphorylation regulation of acyl-coa biosynthetic process positive regulation of endocytosis synaptic vesicle endocytosis excitatory postsynaptic potential regulation of neuronal synaptic plasticity mitochondrial membrane organization negative regulation of mitochondrial electron transport, nadh to ubiquinone chemical synaptic transmission negative regulation of protein phosphorylation negative regulation of exocytosis positive regulation of hydrogen peroxide catabolic process negative regulation of microtubule polymerization calcium ion homeostasis mitochondrial atp synthesis coupled electron transport positive regulation of inositol phosphate biosynthetic process dopamine biosynthetic process synapse organization negative regulation of dopamine metabolic process positive regulation of release of sequestered calcium ion into cytosol negative regulation of apoptotic process regulation of reactive oxygen species metabolic process regulation of neurotransmitter secretion negative regulation of dopamine uptake involved in synaptic transmission negative regulation of transcription by rna polymerase ii microglial cell activation dopamine uptake involved in synaptic transmission response to lipopolysaccharide protein destabilization neutral lipid metabolic process negative regulation of thrombin-activated receptor signaling pathway membrane organization negative regulation of transporter activity negative regulation of cysteine-type endopeptidase activity involved in apoptotic process regulation of phospholipase activity negative regulation of chaperone-mediated autophagy ageing receptor internalization negative regulation of monooxygenase activity fatty acid metabolic process dopamine metabolic process regulation of neuron death positive regulation of apoptotic process synaptic vesicle transport cellular response to oxidative stress phospholipid metabolic process negative regulation of histone acetylation regulation of macrophage activation positive regulation of receptor recycling long-term potentiation apoptotic process supramolecular fiber organization regulation of presynapse assembly positive regulation of inflammatory response positive regulation of neuron death negative regulation of neuron death response to desipramine regulation of transmembrane transporter activity regulation of norepinephrine uptake synaptic vesicle exocytosis snare complex assembly positive regulation of exocytosis protein complex oligomerization protein tetramerization synaptic vesicle priming sources:amigo / quickgoorthologsspecieshumanmouseentrez662220617ensemblensg00000145335ensmusg00000025889uniprotp37840o55042refseq (mrna)nm_000345nm_001146054nm_001146055nm_007308nm_001375285nm_001375286nm_001375287nm_001375288nm_001375290nm_001042451nm_009221refseq (protein)np_000336np_001139526np_001139527np_009292np_001362214np_001362215np_001362216np_001362217np_001362219np_001035916np_033247location (ucsc)chr 4: 89.7 – 89.84 mbchr 6: 60.71 – 60.81 mbpubmed searchwikidataview/edit humanview/edit mouse 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 in the axon terminals of presynaptic neurons. within these terminals, 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. in parkinson's disease and other synucleinopathies, insoluble forms of alpha-synuclein accumulate as inclusions in lewy bodies. familial parkinson's disease is associated with mutations in the -synuclein (snca) gene. in the process of seeded nucleation, alpha-synuclein acquires a cross-sheet structure similar to other amyloids. the human alpha-synuclein protein is made of 140 amino acids. an alpha-synuclein fragment, known as the non-amyloid beta (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. tissue expression alpha-synuclein is a synuclein protein of unknown function 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. in melanocytes, snca protein expression may be regulated by microphthalmia-associated transcription factor (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 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. in the enteric nervous system (ens) first characterisations of asyn aggregates in the ens of pd patients has been performed on autopsied specimens in the late 1980s. it is yet unknown if the microbiome changes associated with pd are consequential to the illness process or main pathophysiology, or both. individuals diagnosed with various synucleinopathies often display constipation and other gi dysfunctions years prior to the onset of movement dysfunction. alpha synuclein potentially connects the gut-brain axis in parkinson's disease patients. common inherited parkinson disease is associated with mutations in the alpha-synuclein (snca) gene. in the process of seeded nucleation, alpha-synuclein acquires a cross-sheet structure similar to other amyloids. the enterobacteriaceae, which are quite common in the human gut, can create curli, which are functional amyloid proteins. the unfolded amyloid csga, which is secreted by bacteria and later aggregates extracellularly to create biofilms, mediates adherence to epithelial cells, and aids in bacteriophage defense, forms the curli fibers. oral injection of curli-producing bacteria can also boost formation and aggregation of the amyloid protein syn in old rats and nematodes. host inflammation responses in the intestinal tract and periphery are modulated by curli exposure. studies in biochemistry show that endogenous, bacterial chaperones of curli are capable of briefly interacting with syn and controlling its aggregation. the clinical and pathological findings support the hypothesis that asyn disease in pd occurs via a gut-brain pathway. for early diagnosis and early management in the phase of creation and propagation of asyn, it is therefore of utmost importance to identify pathogenic asyn in the digestive system, for example, by git biopsies. according to a growing body of research, intestinal dysbiosis may be a major factor in the development of parkinson's disease by encouraging intestinal permeability, gastrointestinal inflammation, and the aggregation and spread of asyn. not just in the cns but in other peripheral tissues as well, such as the git, has physiological asyn expression and its phosphorylated variants, as well. as suggested by borghammer and van den berge (2019), one approach is to recognise the possibility of pd subtypes with various asyn propagation methods, including either a pns-first or cns-first route. while the gi tract has been linked to other neurological disorders such autism spectrum disorder, depression, anxiety, and alzheimer's disease, protein aggregation and/or inflammation in the gut represent a new topic of investigation in synucleinopathies. structure 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. evidence suggests that alpha-synuclein functions as a molecular chaperone in the formation of snare complexes. in particular, it simultaneously binds to phospholipids of the plasma membrane via its n-terminus domain and to synaptobrevin-2 via its c-terminus domain, with increased importance during synaptic activity. indeed, there is growing evidence that alpha-synuclein is involved in the functioning of the neuronal golgi apparatus and vesicle trafficking. apparently, alpha-synuclein is essential for normal development of the cognitive functions. knock-out mice with the targeted inactivation of the expression of alpha-synuclein show impaired spatial learning and working memory. interaction with lipid membranes experimental evidence has been collected on the interaction of alpha-synuclein with membrane and its involvement with membrane composition and turnover. yeast genome screening has found that several genes that deal with lipid metabolism and mitochondrial fusion play a role in alpha-synuclein toxicity. conversely, alpha-synuclein expression levels can affect the viscosity and the relative amount of fatty acids in the lipid bilayer. alpha-synuclein is known to directly bind to lipid membranes, associating with the negatively charged surfaces of phospholipids. alpha-synuclein forms an extended helical structure on small unilamellar vesicles. a preferential binding to small vesicles has been found. the binding of alpha-synuclein to lipid membranes has complex effects on the latter, altering the bilayer structure and leading to the formation of small vesicles. alpha-synuclein has been shown to bend membranes of negatively charged phospholipid vesicles and form tubules from large lipid vesicles. using cryo-em it was shown that these are micellar tubes of ~5-6 nm diameter. alpha-synuclein has also been shown to form lipid disc-like particles similar to apolipoproteins. epr studies have shown that the structure of alpha synuclein is dependent on the binding surface. the protein adopts a broken-helical conformation on lipoprotein particles while it forms an extended helical structure on lipid vesicles and membrane tubes. studies have also suggested a possible antioxidant activity of alpha-synuclein in the membrane. photomicrographs of regions of substantia nigra in a patient showing lewy bodies and lewy neurites in