Alpha-synuclein

From Wikipedia, the free encyclopedia

Synuclein, alpha (non A4 component of amyloid precursor)

PDB rendering based on 1xq8.

Available structures: 1xq8

Identifiers

Symbol(s)

SNCA; PD1; MGC110988; NACP; PARK1; PARK4

External IDs

OMIM: 163890 MGI: 1277151 HomoloGene: 293

Gene ontology
Molecular Function:	• identical protein binding
Cellular Component:	• cytoplasm • synaptosome
Biological Process:	• positive regulation of neurotransmitter secretion • synaptic transmission, dopaminergic • phospholipid metabolic process • anti-apoptosis • central nervous system development • regulation of locomotion • dopamine biosynthetic process • response to drug • regulation of long-term neuronal synaptic plasticity • synaptic vesicle transport

RNA expression pattern

More reference expression data

Orthologs

Human

Mouse

Refseq

NM_000345 (mRNA)
NP_000336 (protein)

NM_001042451 (mRNA)
NP_001035916 (protein)

Location

Chr 4: 90.87 - 90.98 Mb

Chr 6: 60.66 - 60.76 Mb

Pubmed search

[1]

[2]

Alpha-synuclein is a synuclein protein of unknown function primarily found in neural tissue, where it is seen mainly in presynaptic terminals. 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 glial cells.

Recent evidence suggests that alpha-synuclein functions as a molecular chaperone in the formation of SNARE complexes.

Alpha-synuclein is specifically upregulated in a discrete population of presynaptic terminals of the songbird brain during a period of song-acquisition-related synaptic rearrangement.^[1]

Normally an unstructured soluble protein, alpha-synuclein can aggregate to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Alpha-synuclein is the primary structural component of Lewy body fibrils. In addition, an alpha-synuclein fragment, known as the non-Abeta component (NAC), is found in amyloid plaques in Alzheimer's disease.

There is considerable uncertainty on the aggregation mechanism of alpha-synuclein. There is some evidence of a structured intermediate rich in beta structure that can be the precursor of aggregation and, ultimately, Lewy bodies.^[2] ^[3] A single molecule study in 2008 suggests alpha-synuclein exists as a mix of unstructured, alpha-helix and beta-sheet rich conformers in equilibrium. Mutations or buffer conditions known to improve aggregation strongly increase the population of the beta conformer, thus suggesting this could be a conformation related to pathogenetic aggregation^[4] .

In rare cases of familial forms of Parkinson's disease there is a mutation in the gene coding for alpha-synuclein. Three point mutations have been identified thus far: A53T, A30P and E46K. In addition, duplication and triplication of the gene appear to be the cause of Parkinson's disease in other lineages.

Antibodies against alpha-synuclein have replaced antibodies against ubiquitin as the gold standard for immunostaining of Lewy bodies.

1 See also
2 References
3 Further reading
4 External links

[edit] See also

Synuclein
Contursi Terme - the village in Italy where a mutation in the α-synuclein gene led to a family history of Parkinson's disease

[edit] References

^ George JM, Jin H, Woods WS, Clayton DF. (1995) Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 15:361-372. PMID 7646890
^ Vladimir N.Uversky, Jie Li, Anthony L. Fink Evidence for a partially folded intermediate in alpha-Synuclein Fibril Formation; J.Biol.Chem. 2001; 276(14), 10737-10744
^ Kim HY, Heise H, Fernandez CO, Baldus M, Zweckstetter M Correlation of Amyloid fibril beta-structure with the unfolded state of alpha-synuclein Chembiochem 2007; 8: 1671–1674.
^ Massimo Sandal, Francesco Valle, Isabella Tessari, Stefano Mammi, Elisabetta Bergantino, Francesco Musiani, Marco Brucale, Luigi Bubacco, Bruno Samorì Conformational Equilibria in Monomeric α-Synuclein at the Single-Molecule Level; PLoS Biology 2008;6(1): e6

[edit] Further reading

Polymeropoulos M, Lavedan C, Leroy E et al (1997). "Mutation in the alpha-synuclein gene identified in families with Parkinson's disease". Science 276 (5321): 2045-7. doi:10.1126/science.276.5321.2045. PMID 9197268.

Neumann M, Kahle P, Giasson B et al (2002). "Misfolded proteinase K-resistant hyperphosphorylated alpha-synuclein in aged transgenic mice with locomotor deterioration and in human alpha-synucleinopathies". J. Clin. Invest. 110 (10): 1429-39. PMID 12438441.

Sandra Blakeslee: In Folding Proteins, Clues to Many Diseases. In: The New York Times, May 27, 2002

George JM (2001). "The synucleins". Genome Biology 3 (1): reviews3002.1-3002.6. doi:10.1186/gb-2001-3-1-reviews3002. PMID 11806835.
Lavedan C (1998). "The synuclein family.". Genome Res. 8 (9): 871-80. PMID 9750188.
Ozawa T, Wakabayashi K, Oyanagi K (2002). "[Recent progress in the research of multiple system atrophy with special references to alpha-synuclein and suprachiasmatic nucleus]". No To Shinkei 54 (2): 111-7. PMID 11889756.
Cole NB, Murphy DD (2002). "The cell biology of alpha-synuclein: a sticky problem?". Neuromolecular Med. 1 (2): 95-109. PMID 12025860.
Iwatsubo T (2002). "[alpha-synuclein and Parkinson's disease]". Seikagaku 74 (6): 477-82. PMID 12138709.
Trojanowski JQ, Lee VM (2002). "Parkinson's disease and related synucleinopathies are a new class of nervous system amyloidoses.". Neurotoxicology 23 (4-5): 457-60. doi:10.1016/S0161-813X(02)00065-7. PMID 12428717.
Alves da Costa C (2003). "Recent advances on alpha-synuclein cell biology: functions and dysfunctions.". Curr. Mol. Med. 3 (1): 17-24. PMID 12558071.
Di Rosa G, Puzzo D, Sant'Angelo A, et al. (2004). "Alpha-synuclein: between synaptic function and dysfunction.". Histol. Histopathol. 18 (4): 1257-66. PMID 12973692.
Baptista MJ, Cookson MR, Miller DW (2004). "Parkin and alpha-synuclein: opponent actions in the pathogenesis of Parkinson's disease.". The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 10 (1): 63-72. doi:10.1177/1073858403260392. PMID 14987449.
Kim S, Seo JH, Suh YH (2004). "Alpha-synuclein, Parkinson's disease, and Alzheimer's disease.". Parkinsonism Relat. Disord. 10 Suppl 1: S9-13. doi:10.1016/j.parkreldis.2003.11.005. PMID 15109581.
Sidhu A, Wersinger C, Vernier P (2004). "alpha-Synuclein regulation of the dopaminergic transporter: a possible role in the pathogenesis of Parkinson's disease.". FEBS Lett. 565 (1-3): 1-5. doi:10.1016/j.febslet.2004.03.063. PMID 15135042.
Vekrellis K, Rideout HJ, Stefanis L (2004). "Neurobiology of alpha-synuclein.". Mol. Neurobiol. 30 (1): 1-21. doi:10.1385/MN:30:1:001. PMID 15247485.
Chiba-Falek O, Nussbaum RL (2004). "Regulation of alpha-synuclein expression: implications for Parkinson's disease.". Cold Spring Harb. Symp. Quant. Biol. 68: 409-15. PMID 15338643.
Pankratz N, Foroud T (2005). "Genetics of Parkinson disease.". NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics 1 (2): 235-42. PMID 15717024.
Singleton AB (2005). "Altered alpha-synuclein homeostasis causing Parkinson's disease: the potential roles of dardarin.". Trends Neurosci. 28 (8): 416-21. doi:10.1016/j.tins.2005.05.009. PMID 15955578.
Lee HG, Zhu X, Takeda A, et al. (2006). "Emerging evidence for the neuroprotective role of alpha-synuclein.". Exp. Neurol. 200 (1): 1-7. doi:10.1016/j.expneurol.2006.04.024. PMID 16780837.
Giorgi FS, Bandettini di Poggio A, Battaglia G, et al. (2006). "A short overview on the role of alpha-synuclein and proteasome in experimental models of Parkinson's disease.". J. Neural Transm. Suppl. (70): 105-9. PMID 17017516.