Alpha Synuclein ~ Definition TOP 5 : Overview and Research Papers on Alpha Synucleins
Definition-I of Alpha Synuclein
Alpha-synuclein: One in a family of structurally related proteins that are prominently expressed in the central nervous system. Aggregated alpha-synuclein proteins form brain lesions that are hallmarks of some neurodegenerative diseases (synucleinopathies). The gene for alpha-synuclein, which is called SNCA, is on chromosome 4q21. One form of hereditary Parkinson disease is due to mutations in SNCA. Another form of hereditary Parkinson disease is due to a triplication of SNCA. See also: Parkinson disease gene. http://www.medterms.com/script/main/art.asp?articlekey=25040
Definition-II of Alpha Synuclein
A protein found inside nerve cells that is the predominant component of Lewy bodies http://alzheimers.about.com/od/glossary/g/alphasynuclein.htm
Definition-III of Alpha Synuclein A brain presynaptic protein that is expressed also in other tissues, but at very low levels. It is highly conserved, rodent and zebrafish α synucleins being 95% and 86% identical to human. Some mutations are linked to familial Parkinson's disease. http://www.answers.com/topic/synuclein#ixzz1W1QA4d70
Definition-IV of Alpha Synuclein
A synuclein that is a major component of LEWY BODIES that plays a role in neurodegeneration and neuroprotection. Other names alpha Synuclein; Non AB Component of AD Amyloid Protein; Non-AB Component of AD Amyloid Protein http://www.reference.md/files/D051/mD051844.html
Definition-V of Alpha Synuclein
A family of homologous proteins of low MOLECULAR WEIGHT that are predominately expressed in the BRAIN and that have been implicated in a variety of human diseases. They were originally isolated from CHOLINERGIC FIBERS of TORPEDO.
beta-Synuclein Definition: A synuclein that is closely related to ALPHA-SYNUCLEIN. It may play a neuroprotective role against some of the toxic effects of aggregated ALPHA-SYNUCLEIN.
alpha synuclein Definition: brain protein of unknown function; mutation is associated with Parkinson's disease.
alpha-Synuclein Definition: A synuclein that is a major component of LEWY BODIES that plays a role in neurodegeneration and neuroprotection.
Synuclein Gamma Definition: Encoded by human SNCG Gene (Synuclein Family), the highly conserved 127-amino acid 13 kD cytoplasmic Gamma-Synuclein is similar to the amyloid protein nonamyloid beta fragment and to alpha-synuclein and beta-synuclein. SNCG is expressed in brain, heart, skeletal muscle, ovary, testis, colon, spleen, pancreas, kidney and lung. Gamma-Synuclein seems to play a role in neurofilament network integrity and may modulate axonal architecture; it may increase the susceptibility of neurofilament-H to calcium-dependent proteases and may also modulate the keratin network in skin. Phosphorylation by GRK5 appears to occur on residues distinct from other kinase target residues. Gamma-Synuclein is likely involved in the pathogenesis of neurodegenerative diseases and SNCG is expressed at very high level in advanced infiltrating breast cancer. (from Swiss-Prot, OMIM, and NCI)
gamma-Synuclein Definition: A homolog of ALPHA-SYNUCLEIN that plays a role in neurofilament network integrity. It is overexpressed in a variety of human NEOPLASMS and may be involved in modulating AXON architecture during EMBRYONIC DEVELOPMENT and in the adult. Gamma-Synuclein may also activate SIGNAL TRANSDUCTION PATHWAYS associated with ETS-DOMAIN PROTEIN ELK-
Synuclein Family Definition: Small, soluble Synuclein Family proteins are a group of highly conserved post-transcriptionally modified Alpha, Beta, and Gamma proteins expressed primarily in neural tissue and often localized near synaptic vesicles. Synucleins may inhibit PLD2 and regulate vesicular transport. In the N-terminal portion, synucleins have a conserved repeated 11-residue amphipathic alpha-helical motif similar to the lipid-binding A2 domain of apolipoproteins. Synucleins also contain several repeated variations of a highly conserved KTKEGV domain, also present in rho family proteins. In brain, synucleins may be phosphorylated by Ca2+ calmodulin protein kinase II. Synucleins are overexpressed in breast carcinomas and mutations are associated with neurodegenerative illnesses.
Overview
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.
Tissue expression
Alpha-synuclein is a synuclein protein of unknown function primarily found in neural tissue, making 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
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.
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.
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.
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.
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.
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.
Alpha-synuclein is known to directly bind to lipid membranes, associating with the negatively charged surfaces of phospholipids.[21] A preferential binding to small vesicles has been found.[22] 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.[23] Alpha-synuclein has been shown to bend membranes of negatively charged phospholipid vesicles and form tubules from large lipid vesicles.[24] Studies have also suggested a possible antioxidant activity of alpha-synuclein in the membrane.
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
Residues 61-95: A central hydrophobic region which includes the non-amyloid component (NAC) region, involved in protein aggregation
Residues 96-140: an highly acidic and proline-rich region which has no distinct structural propensity
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[27] and multiple system atrophy.[28] These disorders are known as synucleinopathies. Alpha-synuclein is the primary structural component of Lewy body fibrils. Occasionally, Lewy bodies contain tau protein,[29] however, alpha-synuclein and tau constitute two distinctive subsets of filaments in the same inclusion bodies.[30] Alpha-synuclein pathology is also found in both sporadic and familial cases with 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.[32] 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.[33] The Epstein-Barr virus has been implicated in these disorders.
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[35] and E46K.[36] In addition, duplication and triplication of the gene appear to be the cause of Parkinson's disease in other lineages. 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.
Antibodies against alpha-synuclein have replaced antibodies against ubiquitin as the gold standard for immunostaining of Lewy bodies.
Events in α-synuclein toxicity.[38] 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.
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