alpha-synuclein; non-A beta component of AD amyloid; non-A4 component of amyloid; NACP (SNCA, NACP, PARK1)
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Function
- inhibits movement of proteins from endoplasmic reticulum to Golgi[7]
- regulation of dopamine transport & release[8]
- degradation of alpha-synuclein is facilitated by parkin & ubiquitin
- reduces neuronal responsiveness to various apoptotic stimuli, leading to a decreased caspase-3 activation
- phosphorylated, predominantly on Ser
- phosphorylation by CK1 appears to occur on residues distinct from the residue phosphorylated by other kinases
- phosphorylated on Tyr-125 by a PTK2B-dependent pathway upon osmotic stress
- ubiquitinated, the predominant conjugate is the diubiquitinated form (putative)
- soluble monomer which can form filamentous aggregates
- interacts with UCHL1 (putative)
- 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:
- 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
More general terms
Additional terms
References
- ↑ Ueda et al PNAS 90:11282-86 1993
- ↑ Brookes AJ & St Clair D Synuclein proteins and Alzheimer's disease. TINS 17:404 1994 PMID: https://www.ncbi.nlm.nih.gov/pubmed/7530877
- ↑ Giasson BI et al Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290:985-9, 2000 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11062131
- ↑ Lee V. In: Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
- ↑ 5.0 5.1 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: https://www.ncbi.nlm.nih.gov/pubmed/11431533
- ↑ Entrez Gene http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=6622
- ↑ 7.0 7.1 7.2 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
- ↑ 8.0 8.1 UniProt http://www.uniprot.org/uniprot/P37840.html
- ↑ 9.0 9.1 9.2 9.3 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
- ↑ 10.0 10.1 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/30862700 <Internet> http://stke.sciencemag.org/content/12/572/eaau4543
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/38048087 PMCID: PMC10696516 Free PMC article https://jamanetwork.com/journals/jamaneurology/fullarticle/2812433
- ↑ genereviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=snca
- ↑ NIEHS-SNPs http://egp.gs.washington.edu/data/snca/
Database
- UniProt: http://www.uniprot.org/uniprot/P37840.html
- Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=6622
- Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:6622
- OMIM: https://mirror.omim.org/entry/127750
- OMIM: https://mirror.omim.org/entry/163890
- OMIM: https://mirror.omim.org/entry/168600
- OMIM: https://mirror.omim.org/entry/168601
- OMIM: https://mirror.omim.org/entry/605543