Alpha-synuclein

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Synuclein, alpha (non A4 component of amyloid precursor)

PDB rendering based on 1xq8.
Identifiers
Symbols SNCA; MGC110988; NACP; PARK1; PARK4; PD1
External IDs OMIM: 163890 MGI: 1277151 HomoloGene: 293 GeneCards: SNCA Gene
RNA expression pattern
PBB GE SNCA 204466 s at tn.png
PBB GE SNCA 204467 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 6622 20617
Ensembl ENSG00000145335 ENSMUSG00000025889
UniProt P37840 Q3U130
RefSeq (mRNA) NM_000345.3 NM_001042451
RefSeq (protein) NP_000336.1 NP_001035916
Location (UCSC) Chr 4:
90.65 – 90.76 Mb		 Chr 6:
60.68 – 60.78 Mb
PubMed search [2] [3]

Alpha-synuclein is a protein that, in humans, is encoded by the SNCA gene.[1][2][3] An alpha-synuclein fragment, known as the non-Abeta component (NAC) of Alzheimer's disease amyloid, originally found in an amyloid-enriched fraction, is shown to be a fragment of its precursor protein, NACP, by cloning of the full-length cDNA.[1] It was later determined that NACP was the human homologue of Torpedo synuclein. Therefore, NACP is now referred to as human alpha-synuclein.

Contents

[edit] Tissue expression

Alpha-synuclein is a synuclein protein of unknown function primarily found in neural tissue, making up up to 1% of all proteins in the cytosol.[4] 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. In melanocytic cells, SNCA protein expression may be regulated by MITF.[5]

It has been established that alpha-synuclein is extensively localized in the nucleus of mammalian brain neurons, suggesting a role of alpha-synuclein in the nucleus.[6] Synuclein is however found predominantly in the presynaptic termini, in both free or membrane-bound forms,[7] with roughly 15% of synuclein being membrane-bound in any moment in neurons.[8]

Recently, it has been shown that alpha-synuclein is localized in neuronal mitochondria.[9][10] Alpha-synuclein is highly expressed in the mitochondria in olfactory bulb, hippocampus, striatum,and thalamus, where the cytosolic alpha-synuclein is also rich. However, the cerebral cortex and cerebellum are two exceptions, which contain rich cytosolic alpha-synuclein but very low levels of mitochondrial alpha-synuclein. It has been shown that alpha-synuclein is localized in the inner membrane of mitochondria, and that the inhibitory effect of alpha-synuclein on complex I activity of mitochondrial respiratory chain is dose-dependent. Thus, it is suggested that alpha-synuclein in mitochondria is differentially expressed in different brain regions and the background levels of mitochondrial alpha-synuclein may be a potential factor affecting mitochondrial function and predisposing some neurons to degeneration.[10]

At least three isoforms of synuclein are produced through alternative splicing.[11] The majority form of the protein, and the one most investigated, is the full 140 aminoacids-long transcript. Other isoforms are alpha-synuclein-126, where exon 3 is lost and lacks residues 41-54; and alpha-synuclein-112,[12] which lacks residue 103-130 due to loss of exon 5.[11]

[edit] Functions

Alpha-synuclein is specifically upregulated in a discrete population of presynaptic terminals of the brain during a period of acquisition-related synaptic rearrangement.[13] It has been shown that alpha-synuclein significantly interacts with tubulin,[14] and that alpha-synuclein may have an activity as potential microtubule-associated protein like tau.[15]

Recent evidence suggests that alpha-synuclein functions as a molecular chaperone in the formation of SNARE complexes.[16][17][18] Indeed, there is growing evidence that alpha-synuclein is involved in the functioning of the neuronal Golgi apparatus and vesicle trafficking.[19]

[edit] Interaction with lipid membranes

Experimental evidence has been collected on the interaction of alpha-synuclein with membrane and its involvement with membrane composition and turnover. Yeast genome screening has found that several genes that deal with lipid metabolism play a role in alpha-synuclein toxicity.[20] Conversely, alpha-synuclein expression levels can affect the viscosity and the relative amount of fatty acids in the lipid bilayer.[21]

Alpha-synuclein is known to directly bind to lipid membranes, associating with the negatively charged surfaces of phospholipids.[21] Alpha-synuclein forms an extended helical structure on small unilamellar vesicles.[22] A preferential binding to small vesicles has been found.[23] The binding of alpha-synuclein to lipid membranes has complex effects on the latter, altering the bilayer structure and leading to the formation of small vesicles.[24] Alpha-synuclein has been shown to bend membranes of negatively charged phospholipid vesicles and form tubules from large lipid vesicles.[25] Studies have also suggested a possible antioxidant activity of alpha-synuclein in the membrane.[26]

[edit] Sequence

Alpha-synuclein primary structure is usually divided in three distinct domains:

  • Residues 1-60: An amphipathic N-terminal region dominated by four 11-residue repeats including the consensus sequence KTKEGV. This sequence has a structural alpha helix propensity similar to apolipoproteins-binding domains[27]
  • Residues 61-95: A central hydrophobic region which includes the non-amyloid component (NAC) region, involved in protein aggregation[1]
  • Residues 96-140: an highly acidic and proline-rich region which has no distinct structural propensity

[edit] Clinical significance

Positive α-Synuclein staining of a Lewy body in a patient with Parkinson's disease.

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[28] and multiple system atrophy.[29] These disorders are known as synucleinopathies. Alpha-synuclein is the primary structural component of Lewy body fibrils. Occasionally, Lewy bodies contain tau protein,[30] however, alpha-synuclein and tau constitute two distinctive subsets of filaments in the same inclusion bodies.[31] Alpha-synuclein pathology is also found in both sporadic and familial cases with Alzheimer's disease.[32]

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.[33] 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.[34] The Epstein-Barr virus has been implicated in these disorders.[35]

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[36] and E46K.[37] Genomic duplication and triplication of the gene appear to be a rare cause of Parkinson's disease in other lineages, although more common than point mutations.[38] Hence certain mutations of alpha-synuclein may cause it to form amyloid-like fibrils that contribute to Parkinson's disease.

It was previously believed that α-synuclein was natively unfolded but new evidence suggests that unmutated α-synuclein forms a stably folded tetramer that resists aggregation.[39]

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

Events in α-synuclein toxicity.[40] The central panel shows the major pathway for protein aggregation. Monomeric α-synuclein is natively unfolded in solution but can also bind to membranes in an α-helical form. It seems likely that these two species exist in equilibrium within the cell, although this is unproven. From in vitro work, it is clear that unfolded monomer can aggregate first into small oligomeric species that can be stabilized by β-sheet-like interactions and then into higher molecular weight insoluble fibrils. In a cellular context, there is some evidence that the presence of lipids can promote oligomer formation: α-synuclein can also form annular, pore-like structures that interact with membranes. The deposition of α-synuclein into pathological structures such as Lewy bodies is probably a late event that occurs in some neurons. On the left hand side are some of the known modifiers of this process. Electrical activity in neurons changes the association of α-synuclein with vesicles and may also stimulate polo-like kinase 2 (PLK2), which has been shown to phosphorylate α-synuclein at Ser129. Other kinases have also been proposed to be involved. As well as phosphorylation, truncation through proteases such as calpains, and nitration, probably through nitric oxide (NO) or other reactive nitrogen species that are present during inflammation, all modify synuclein such that it has a higher tendency to aggregate. The addition of ubiquitin (shown as a black spot) to Lewy bodies is probably a secondary process to deposition. On the right are some of the proposed cellular targets for α-synuclein mediated toxicity, which include (from top to bottom) ER-golgi transport, synaptic vesicles, mitochondria and lysosomes and other proteolytic machinery. In each of these cases, it is proposed that α-synuclein has detrimental effects, listed below each arrow, although at this time it is not clear if any of these are either necessary or sufficient for toxicity in neurons.

Certain sections of the alpha-synuclein protein may play a role in the tauopathies.[41]

[edit] Protein-protein interactions

Alpha-synuclein has been shown to interact with

[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

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