Alpha-synuclein (SNCA)

The protein contains 140 amino acids for an estimated molecular weight of 14460 Da.

 

Neuronal protein that plays several roles in synaptic activity such as regulation of synaptic vesicle trafficking and subsequent neurotransmitter release. Participates as a monomer in synaptic vesicle exocytosis by enhancing vesicle priming, fusion and dilation of exocytotic fusion pores (PubMed:28288128, PubMed:30404828). Mechanistically, acts by increasing local Ca(2+) release from microdomains which is essential for the enhancement of ATP-induced exocytosis (PubMed:30404828). Acts also as a molecular chaperone in its multimeric membrane-bound state, assisting in the folding of synaptic fusion components called SNAREs (Soluble NSF Attachment Protein REceptors) at presynaptic plasma membrane in conjunction with cysteine string protein-alpha/DNAJC5 (PubMed:20798282). This chaperone activity is important to sustain normal SNARE-complex assembly during aging (PubMed:20798282). Plays also a role in the regulation of the dopamine neurotransmission by associating with the dopamine transporter (DAT1) and thereby modulating its activity (PubMed:26442590). (updated: Feb. 13, 2019)

Protein identification was indicated in the following studies:

  1. Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
  2. Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
  3. Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
  4. Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
  5. D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

PublicationIdentification 1Uniprot mapping 2Not mapped /
Obsolete
TrEMBLSwiss-Prot
Goodman (2013)2289 (gene list)227853205992269
Lange (2014)123412347281224
Hegedus (2015)2638262202352387
Wilson (2016)165815281702911068
d'Alessandro (2017)18261817201815
Bryk (2017)20902060101081942
Chu (2018)18531804553621387

1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

This protein is annotated as membranous in Gene Ontology.


Interpro domains
Total structural coverage: 100%
Model score: 100
No model available.

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VariantDescription
PARK1
PARK1 and DLB
PARK1
PARK1

Biological Process

Activation of cysteine-type endopeptidase activity involved in apoptotic process GO Logo
Adult locomotory behavior GO Logo
Aging GO Logo
Amyloid fibril formation GO Logo
Behavioral response to cocaine GO Logo
Cellular protein metabolic process GO Logo
Cellular response to copper ion GO Logo
Cellular response to epinephrine stimulus GO Logo
Cellular response to fibroblast growth factor stimulus GO Logo
Cellular response to oxidative stress GO Logo
Chemical synaptic transmission GO Logo
Dopamine biosynthetic process GO Logo
Dopamine uptake involved in synaptic transmission GO Logo
Excitatory postsynaptic potential GO Logo
Extracellular fibril organization GO Logo
Fatty acid metabolic process GO Logo
Long-term synaptic potentiation GO Logo
Microglial cell activation GO Logo
Mitochondrial ATP synthesis coupled electron transport GO Logo
Mitochondrial membrane organization GO Logo
Negative regulation of apoptotic process GO Logo
Negative regulation of chaperone-mediated autophagy GO Logo
Negative regulation of cysteine-type endopeptidase activity involved in apoptotic process GO Logo
Negative regulation of dopamine metabolic process GO Logo
Negative regulation of dopamine uptake involved in synaptic transmission GO Logo
Negative regulation of exocytosis GO Logo
Negative regulation of histone acetylation GO Logo
Negative regulation of microtubule polymerization GO Logo
Negative regulation of mitochondrial electron transport, NADH to ubiquinone GO Logo
Negative regulation of monooxygenase activity GO Logo
Negative regulation of neuron apoptotic process GO Logo
Negative regulation of neuron death GO Logo
Negative regulation of norepinephrine uptake GO Logo
Negative regulation of platelet-derived growth factor receptor signaling pathway GO Logo
Negative regulation of protein kinase activity GO Logo
Negative regulation of protein phosphorylation GO Logo
Negative regulation of serotonin uptake GO Logo
Negative regulation of thrombin-activated receptor signaling pathway GO Logo
Negative regulation of transcription by RNA polymerase II GO Logo
Negative regulation of transporter activity GO Logo
Neutral lipid metabolic process GO Logo
Oxidation-reduction process GO Logo
Phospholipid metabolic process GO Logo
Positive regulation of apoptotic process GO Logo
Positive regulation of endocytosis GO Logo
Positive regulation of exocytosis GO Logo
Positive regulation of glutathione peroxidase activity GO Logo
Positive regulation of hydrogen peroxide catabolic process GO Logo
Positive regulation of inflammatory response GO Logo
Positive regulation of inositol phosphate biosynthetic process GO Logo
Positive regulation of neuron death GO Logo
Positive regulation of neurotransmitter secretion GO Logo
Positive regulation of peptidyl-serine phosphorylation GO Logo
Positive regulation of protein serine/threonine kinase activity GO Logo
Positive regulation of receptor recycling GO Logo
Positive regulation of release of sequestered calcium ion into cytosol GO Logo
Positive regulation of SNARE complex assembly GO Logo
Protein destabilization GO Logo
Protein tetramerization GO Logo
Receptor internalization GO Logo
Regulation of acyl-CoA biosynthetic process GO Logo
Regulation of dopamine secretion GO Logo
Regulation of glutamate secretion GO Logo
Regulation of locomotion GO Logo
Regulation of long-term neuronal synaptic plasticity GO Logo
Regulation of macrophage activation GO Logo
Regulation of neuron death GO Logo
Regulation of norepinephrine uptake GO Logo
Regulation of phospholipase activity GO Logo
Regulation of presynapse assembly GO Logo
Regulation of reactive oxygen species biosynthetic process GO Logo
Regulation of synaptic vesicle recycling GO Logo
Regulation of transmembrane transporter activity GO Logo
Response to desipramine GO Logo
Response to drug GO Logo
Response to interferon-gamma GO Logo
Response to interleukin-1 GO Logo
Response to iron(II) ion GO Logo
Response to lipopolysaccharide GO Logo
Response to magnesium ion GO Logo
SNARE complex assembly GO Logo
Supramolecular fiber organization GO Logo
Synapse organization GO Logo
Synaptic vesicle endocytosis GO Logo
Synaptic vesicle exocytosis GO Logo
Synaptic vesicle priming GO Logo
Synaptic vesicle transport GO Logo

The reference OMIM entry for this protein is 127750

Dementia, lewy body; dlb
Lewy body dementia
Diffuse lewy body disease diffuse lewy body disease with gaze palsy, included
Lewy body variant of alzheimer disease, included

A number sign (#) is used with this entry because dementia with Lewy bodies (DLB) can be caused by mutation in the alpha-synuclein (SNCA; 163890) or beta-synuclein (SNCB; 602569) genes. Familial Parkinson disease-1 (PARK1; 168601) is associated with mutation in the SNCA gene. The epsilon-4 allele of the APOE gene (107741) and the B allele of the CYP2D6 gene (124030), a cytochrome P-450 monooxygenase, have also been implicated in DLB. A mutation in the prion protein gene (PRNP; see 176640.0017) has been identified in 1 patient with DLB. Some patients with a diagnosis consistent with Lewy body disease or dementia have mutations in the LRRK2 gene (609007), which is associated with Parkinson disease-8 (PARK8; 607060) (Giasson et al., 2006; Ross et al., 2006). One family with a mutation in the PSEN2 gene (600759.0009), usually associated with Alzheimer disease-4 (AD4; 606889), had clinical and neuropathologic findings consistent with DLB (Piscopo et al., 2008).

DESCRIPTION

Dementia with Lewy bodies (DLB) is a neurodegenerative disorder clinically characterized by dementia and parkinsonism, often with fluctuating cognitive function, visual hallucinations, falls, syncopal episodes, and sensitivity to neuroleptic medication. Pathologically, Lewy bodies are present in a pattern more widespread than usually observed in Parkinson disease (see PD; 168600). Alzheimer disease (AD; 104300)-associated pathology and spongiform changes may also be seen (McKeith et al., 1996; Mizutani, 2000; McKeith et al., 2005).

CLINICAL FEATURES

Ishikawa et al. (1997) reported 2 unrelated families with familial autosomal dominant diffuse Lewy body disease. In family A, 4 patients over 3 generations presented with parkinsonism, vertical ocular limitation, progressive dementia, and delusions or visual hallucinations. Two of the patients developed neuroleptic malignant syndrome (NMS). Family S had 3 affected members over 3 generations. One was examined in detail and presented with parkinsonism and progressive dementia and later developed NMS. In a member of family S reported by Ishikawa et al. (1997), Ishikawa et al. (2005) identified a mutation in the PSEN1 gene (104311.0032). No mutations were identified in the SNCA gene. The phenotype was an overlap between DLB and Alzheimer disease with spastic paraparesis (607822). Denson et al. (1997) reported 10 individuals with Lewy body disease in 3 successive generations of 2 closely intermarried families. The phenotype was variable: 4 patients displayed parkinsonian features only, 3 had dementia only, and 3 had combined parkinsonism and dementia. Mean age of onset was 62 years. Linkage studies were inconclusive. Wakabayashi et al. (1998) described a Japanese family with parkinsonism and later-onset dementia. The proband developed parkinsonism at the age of 61 years, followed by dementia starting when she was 67. Her uncle, who was also her husband, died at the age of 78 years after 7- and 5-year histories of parkinsonism and dementia, respectively. Her 2 sons developed similar parkinsonism at the ages of 39 and 28 years and also suffered later-onset dementia. The apolipoprotein E genotype of the proband, her uncle, and 1 of their sons was E3/4 and that of the other son was E4/4. The authors concluded that this represented autosomal dominant diffuse Lewy body disease. Ohara et al. (1999) presented a familial case of dementia with Lewy bodies in 3 sibs, born of first-cousin parents, who demonstrated progress ... More on the omim web site

Subscribe to this protein entry history

Feb. 22, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 127750 was added.

Jan. 27, 2016: Protein entry updated
Automatic update: model status changed

Jan. 24, 2016: Protein entry updated
Automatic update: model status changed