Alpha-synuclein

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. [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]

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. [Vladimir N.Uversky, Jie Li, Anthony L. Fink [http://www.jbc.org/cgi/content/full/276/14/10737 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 [http://www.ncbi.nlm.nih.gov/pubmed/17722123?dopt=Abstract Correlation of Amyloid fibril beta-structure with the unfolded state of alpha-synuclein] Chembiochem 2007; 8: 1671–1674.] 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 [Massimo Sandal, Francesco Valle, Isabella Tessari, Stefano Mammi, Elisabetta Bergantino, Francesco Musiani, Marco Brucale, Luigi Bubacco, Bruno Samorì [http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0060006 Conformational Equilibria in Monomeric α-Synuclein at the Single-Molecule Level] ; "PLoS Biology" 2008;6(1): e6] .

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.

ee 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

References

Further reading

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

*cite journal |author=George JM |title=The synucleins |journal=Genome Biology |volume=3 |issue=1 |pages=reviews3002.1–3002.6 |year=2001 |pmid=11806835 |doi=10.1186/gb-2001-3-1-reviews3002PBB_Further_reading
citations =
*cite journal | author=Lavedan C |title=The synuclein family |journal=Genome Res. |volume=8 |issue= 9 |pages= 871–80 |year= 1998 |pmid= 9750188 |doi=
*cite journal | author=Ozawa T, Wakabayashi K, Oyanagi K |title= [Recent progress in the research of multiple system atrophy with special references to alpha-synuclein and suprachiasmatic nucleus] |journal=No To Shinkei |volume=54 |issue= 2 |pages= 111–7 |year= 2002 |pmid= 11889756 |doi=
*cite journal | author=Cole NB, Murphy DD |title=The cell biology of alpha-synuclein: a sticky problem? |journal=Neuromolecular Med. |volume=1 |issue= 2 |pages= 95–109 |year= 2002 |pmid= 12025860 |doi=
*cite journal | author=Iwatsubo T |title= [alpha-synuclein and Parkinson's disease] |journal=Seikagaku |volume=74 |issue= 6 |pages= 477–82 |year= 2002 |pmid= 12138709 |doi=
*cite journal | author=Trojanowski JQ, Lee VM |title=Parkinson's disease and related synucleinopathies are a new class of nervous system amyloidoses |journal=Neurotoxicology |volume=23 |issue= 4-5 |pages= 457–60 |year= 2002 |pmid= 12428717| doi=10.1016/S0161-813X(02)00065-7
*cite journal | author=Alves da Costa C |title=Recent advances on alpha-synuclein cell biology: functions and dysfunctions |journal=Curr. Mol. Med. |volume=3 |issue= 1 |pages= 17–24 |year= 2003 |pmid= 12558071 |doi=
*cite journal | author=Di Rosa G, Puzzo D, Sant'Angelo A, "et al." |title=Alpha-synuclein: between synaptic function and dysfunction |journal=Histol. Histopathol. |volume=18 |issue= 4 |pages= 1257–66 |year= 2004 |pmid= 12973692 |doi=
*cite journal | author=Baptista MJ, Cookson MR, Miller DW |title=Parkin and alpha-synuclein: opponent actions in the pathogenesis of Parkinson's disease |journal=The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry |volume=10 |issue= 1 |pages= 63–72 |year= 2004 |pmid= 14987449 |doi= 10.1177/1073858403260392
*cite journal | author=Kim S, Seo JH, Suh YH |title=Alpha-synuclein, Parkinson's disease, and Alzheimer's disease |journal=Parkinsonism Relat. Disord. |volume=10 Suppl 1 |issue= |pages= S9–13 |year= 2004 |pmid= 15109581 |doi= 10.1016/j.parkreldis.2003.11.005
*cite journal | author=Sidhu A, Wersinger C, Vernier P |title=alpha-Synuclein regulation of the dopaminergic transporter: a possible role in the pathogenesis of Parkinson's disease |journal=FEBS Lett. |volume=565 |issue= 1-3 |pages= 1–5 |year= 2004 |pmid= 15135042 |doi= 10.1016/j.febslet.2004.03.063
*cite journal | author=Vekrellis K, Rideout HJ, Stefanis L |title=Neurobiology of alpha-synuclein |journal=Mol. Neurobiol. |volume=30 |issue= 1 |pages= 1–21 |year= 2004 |pmid= 15247485| doi=10.1385/MN:30:1:001
*cite journal | author=Chiba-Falek O, Nussbaum RL |title=Regulation of alpha-synuclein expression: implications for Parkinson's disease |journal=Cold Spring Harb. Symp. Quant. Biol. |volume=68 |issue= |pages= 409–15 |year= 2004 |pmid= 15338643 |doi=
*cite journal | author=Pankratz N, Foroud T |title=Genetics of Parkinson disease |journal=NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics |volume=1 |issue= 2 |pages= 235–42 |year= 2005 |pmid= 15717024 |doi=
*cite journal | author=Singleton AB |title=Altered alpha-synuclein homeostasis causing Parkinson's disease: the potential roles of dardarin |journal=Trends Neurosci. |volume=28 |issue= 8 |pages= 416–21 |year= 2005 |pmid= 15955578 |doi= 10.1016/j.tins.2005.05.009
*cite journal | author=Lee HG, Zhu X, Takeda A, "et al." |title=Emerging evidence for the neuroprotective role of alpha-synuclein |journal=Exp. Neurol. |volume=200 |issue= 1 |pages= 1–7 |year= 2006 |pmid= 16780837 |doi= 10.1016/j.expneurol.2006.04.024
*cite journal | author=Giorgi FS, Bandettini di Poggio A, Battaglia G, "et al." |title=A short overview on the role of alpha-synuclein and proteasome in experimental models of Parkinson's disease |journal=J. Neural Transm. Suppl. |volume= |issue= 70 |pages= 105–9 |year= 2006 |pmid= 17017516 |doi=

External links

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