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alpha-synuclein; non-A beta component of AD amyloid; non-A4 component of amyloid; NACP (SNCA, NACP, PARK1)

Function: 1) inhibits movement of proteins from endoplasmic reticulum to Golgi [7] 2) regulation of dopamine transport & release [8] 3) degradation of alpha-synuclein is facilitated by parkin & ubiquitin 4) reduces neuronal responsiveness to various apoptotic stimuli, leading to a decreased caspase-3 activation 5) phosphorylated, predominantly on Ser 6) phosphorylation by CK1 appears to occur on residues distinct from the residue phosphorylated by other kinases 7) phosphorylated on Tyr-125 by a PTK2B-dependent pathway upon osmotic stress 8) ubiquitinated, the predominant conjugate is the diubiquitinated form (putative) 9) soluble monomer which can form filamentous aggregates 10) interacts with UCHL1 (putative) 11) interacts with phospholipase D & histones Structure: - the NAC domain is involved in the fibril formation - the middle region forms the core of the filaments - the C-terminus may regulate aggregation & determine the diameter of the filaments - belongs to the synuclein family Compartment: - cytoplasm, membrane, nucleus - membrane-bound in dopaminergic neurons - also found in the nucleus - appears to be located at the synaptic junction of ChAT-positive magnocellular cholinergic neurons of the nucleus basalis of Meynert & cortical pyramidal neuronscontaining muscarinic receptors that use phospholipase C [PLC] as a 2nd messenger - concentrated in presynaptic nerve terminals Alternative splicing: named isoforms=3; additional isoforms seem to exist Expression: - highest levels of mRNA for synuclein are found in the hippocampus, dentate gyrus, olfactory bulb & tract, & layers II, II, & V of the cerebral neocortex, similar to the distribution of muscarinic receptors M1 & M3 - expressed in low concentrations in all tissues examined except liver - beta-2 adrenergic receptor agonists reduce expression of alpha-synuclein in neuronal cell cultures [9] - conversely beta-blockers increase expression of alpha-synuclein [9] - seems to be mediated by acetylation on Lys-27 of histone-H3, which the promoter region of the SNCA gene appears to be very sensitive to [9] Pathology: - can form filamentous aggregates that are the major non amyloid component of intracellular inclusions in several neurodegenerative diseases (synucleinopathies) - Mn+2 facilitates secretion of misfolded alpha-synuclein through exosomes in cultured dopaminergic neurons [10] - induces fibrillization of microtubule-associated protein tau - phosphorylation of Ser-129 is selective & extensive in synucleinopathy lesions - in vitro, phosphorylation at Ser-129 promoted insoluble fibril formation - non A-beta component (NAC) sequence from aa 61-95, critical for fibril formation in disease states - normally in an unfolded state when unbound to lipid membranes - in disease states, conformation changes & aggregates have a beta sheet structure similar to other amyloid proteins - alpha synuclein deposits in neurodegenerative diseases show Ser-129 phosphorylation - rab 1 in yeast inhibits toxicity of alpha-synuclein [7] - defects in genes which encode alpha-synuclein, parkin & ubiquitin are associated with hereditary Parkinson's disease [5] - alpha-synuclein is a major component of: - Lewy bodies & Lewy neurites in: - Parkinson's disease* - diffuse Lewy body disease - Lewy body variant of Alzheimer's disease* - glial & neuronal cytoplasmic inclusions in multiple system atrophy* - neuronal spheroids in Hallervorden-Spatz disease or neurodegeneration with brain iron accumulation type 1 (NBIA1) - amyloid (senile) plaques - Down's syndrome - Familial cases of Alzheimer's disease * alpha-synuclein in these conditions undergoes Tyr nitration & possibly by di-Tyr cross-linking to generate stable oligomers Laboratory: - alpha-synuclein Ag in tissue - alpha-synuclein seed amplification assay

Interactions

molecular events

Related

alpha synuclein (SCNA) gene alpha-synuclein seed amplification assay; CSF alpha-synuclein (SYNTap test) non-A-beta component of AD amyloid SNCA gene mutation synucleinopathy (includes alpha-synucleinopathy)

General

phosphoprotein synuclein

Properties

SIZE: entity length = 140 aa MW = 14 kD COMPARTMENT: cytoplasm cell nucleus MOTIF: 4 X 11 AA tandem repeats of [EGS]-K-T-K- [EQ]-[GQ]-V-X(4) {20-67} MOTIF: consensus repeat {20-30} consensus repeat {31-41} consensus repeat {42-56} consensus repeat {57-67} Ser phosphorylation site {S87} Tyr phosphorylation site {Y125} Ser phosphorylation site {S129}

Database Correlations

OMIM correlations MORBIDMAP 163890 UniProt P37840 Pfam PF01387 Entrez Gene 6622 Kegg hsa:6622

References

  1. Ueda et al PNAS 90:11282-86 1993
  2. Brookes AJ & St Clair D Synuclein proteins and Alzheimer's disease. TINS 17:404 1994 PMID: 7530877
  3. Giasson BI et al Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290:985-9, 2000 PMID: 11062131
  4. Lee V. In: Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
  5. Journal Watch 22(1):8, 2002 Shimura H et al Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson's disease. Science 293:263, 2001 PMID: 11431533
  6. Entrez Gene :accession 6622
  7. Cooper AA et al, alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neurons in Parkinson's disease models. Science 2006; June 22, http://dx.doi.org/10.1126/science.1129462
  8. UniProt :accession P37840
  9. Lowe D A New Piece of the Parkinson's Puzzle. Science Translational Medicine. Sept 5, 2017 http://blogs.sciencemag.org/pipeline/archives/2017/09/05/a-new-piece-of-the-parkinsons-puzzle
  10. Harischandra DS, Rokad D, Neal ML et al Manganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of alpha-synuclein. Sci. Signal. 12 Mar 2019: Vol. 12, Issue 572, eaau4543 PMID: 30862700 http://stke.sciencemag.org/content/12/572/eaau4543
  11. Yan S, Chang C, Janzen A et al. Neuronally derived extracellular vesicle alpha-synuclein as a serum biomarker for individuals at risk of developing Parkinson disease. JAMA Neurol 2024 Jan 1; 81:59-68. PMID: 38048087 PMCID: PMC10696516 Free PMC article https://jamanetwork.com/journals/jamaneurology/fullarticle/2812433
  12. genereviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=snca
  13. NIEHS-SNPs http://egp.gs.washington.edu/data/snca/

Component-of

molecular complex