Alpha-synuclein
Encyclopedia
Alpha-synuclein is a protein
that, in humans, is encoded by the SNCA gene
. 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. It was later determined that NACP was the human homologue of Torpedo
synuclein. Therefore, NACP is now referred to as human alpha-synuclein.
protein
of unknown function primarily found in neural tissue, making up up to 1% of all proteins in the cytosol
. 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. Synuclein is however found predominantly in the presynaptic termini, in both free or membrane-bound forms, 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. 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
. 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, which lacks residue 103-130 due to loss of exon 5.
in a discrete population of presynaptic terminals of the brain during a period of acquisition-related synaptic rearrangement.
It has been shown that alpha-synuclein significantly interacts with tubulin, 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. Indeed, there is growing evidence that alpha-synuclein is involved in the functioning of the neuronal Golgi apparatus
and vesicle
trafficking.
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. 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. Alpha-synuclein forms an extended helical structure on small unilamellar vesicles. A preferential binding to small vesicles has been found. 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. Alpha-synuclein has been shown to bend membranes of negatively charged phospholipid vesicles and form tubules from large lipid vesicles. Studies have also suggested a possible antioxidant
activity of alpha-synuclein in the membrane.
is usually divided in three distinct domains:
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
. These disorders are known as synucleinopathies. Alpha-synuclein is the primary structural component of Lewy body fibrils. Occasionally, Lewy bodies contain tau protein, however, alpha-synuclein and tau constitute two distinctive subsets of filaments in the same inclusion bodies. 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. 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. 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 mutation
s have been identified thus far: A53T, A30P and E46K. 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. 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.
Certain sections of the alpha-synuclein protein may play a role in the tauopathies.
with
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that, in humans, is encoded by the SNCA gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. An alpha-synuclein fragment, known as the non-Abeta component (NAC) of Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
amyloid
Amyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
, 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. It was later determined that NACP was the human homologue of Torpedo
Torpedo (genus)
Torpedo is a genus of rays, commonly known as electric rays, torpedo rays, or torpedoes. It is the sole genus of the family Torpedinidae. They are slow-moving bottom-dwellers capable of generating electricity as a defense and feeding mechanism...
synuclein. Therefore, NACP is now referred to as human alpha-synuclein.
Tissue expression
Alpha-synuclein is a synucleinSynuclein
Synucleins are a family of soluble proteins common to vertebrates, primarily expressed in neural tissue and in certain tumors.- Family members :The synuclein family includes three known proteins: alpha-synuclein, beta-synuclein, and gamma-synuclein...
protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
of unknown function primarily found in neural tissue, making up up to 1% of all proteins in the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
. It is predominantly expressed in the neocortex
Neocortex
The neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI...
, hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
, substantia nigra
Substantia nigra
The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...
, thalamus
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
, and cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
. 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
Microphthalmia-associated transcription factor
Microphthalmia-associated transcription factor is a basic helix-loop-helix leucine zipper transcription factor involved in melanocyte and osteoclast development.-Clinical significance:...
.
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. Synuclein is however found predominantly in the presynaptic termini, in both free or membrane-bound forms, 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. 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
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
. 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, which lacks residue 103-130 due to loss of exon 5.
Functions
Alpha-synuclein is specifically upregulatedRegulation of gene expression
Gene modulation redirects here. For information on therapeutic regulation of gene expression, see therapeutic gene modulation.Regulation of gene expression includes the processes that cells and viruses use to regulate the way that the information in genes is turned into gene products...
in a discrete population of presynaptic terminals of the brain during a period of acquisition-related synaptic rearrangement.
It has been shown that alpha-synuclein significantly interacts with tubulin, and that alpha-synuclein may have an activity as potential microtubule-associated protein like tau
Tau protein
Tau proteins are proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes...
.
Recent evidence suggests that alpha-synuclein functions as a molecular chaperone in the formation of SNARE
SNARE (protein)
SNARE proteins are a large protein superfamily consisting of more than 60 members in yeast and mammalian cells....
complexes. Indeed, there is growing evidence that alpha-synuclein is involved in the functioning of the neuronal Golgi apparatus
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
and vesicle
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
trafficking.
Interaction with lipid membranes
Experimental evidence has been collected on the interaction of alpha-synuclein with membraneCell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
and its involvement with membrane composition and turnover. Yeast
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
genome screening has found that several genes that deal with lipid metabolism play a role in alpha-synuclein toxicity. 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. Alpha-synuclein forms an extended helical structure on small unilamellar vesicles. A preferential binding to small vesicles has been found. 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. Alpha-synuclein has been shown to bend membranes of negatively charged phospholipid vesicles and form tubules from large lipid vesicles. Studies have also suggested a possible antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
activity of alpha-synuclein in the membrane.
Sequence
Alpha-synuclein primary structurePrimary structure
The primary structure of peptides and proteins refers to the linear sequence of its amino acid structural units. The term "primary structure" was first coined by Linderstrøm-Lang in 1951...
is usually divided in three distinct domains:
- Residues 1-60: An amphipathic N-terminal region dominated by four 11-residue repeats including the consensus sequenceConsensus sequenceIn molecular biology and bioinformatics, consensus sequence refers to the most common nucleotide or amino acid at a particular position after multiple sequences are aligned. A consensus sequence is a way of representing the results of a multiple sequence alignment, where related sequences are...
KTKEGV. This sequence has a structural alpha helixAlpha helixA common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
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 prolineProlineProline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
-rich region which has no distinct structural propensity
Clinical significance
Normally an unstructuredIntrinsically unstructured proteins
Intrinsically unstructured proteins, often referred to as naturally unfolded proteins or disordered proteins, are proteins characterized by lack of stable tertiary structure when the protein exists as an isolated polypeptide chain under physiological conditions in vitro...
soluble protein, alpha-synuclein can aggregate to form insoluble fibrils in pathological conditions characterized by Lewy bodies
Lewy body
Lewy bodies are abnormal aggregates of protein that develop inside nerve cells in Parkinson's disease , Lewy Body Dementia and some other disorders. They are identified under the microscope when histology is performed on the brain....
, such as Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, dementia with Lewy bodies
Dementia with Lewy bodies
Dementia with Lewy bodies , also known under a variety of other names including Lewy body dementia, diffuse Lewy body disease, cortical Lewy body disease, and senile dementia of Lewy type, is a type of dementia closely allied to both Alzheimers and Parkinson's Diseases...
and multiple system atrophy
Multiple system atrophy
Multiple system atrophy is a degenerative neurological disorder. MSA is associated with the degeneration of nerve cells in specific areas of the brain. This cell degeneration causes problems with movement, balance and other autonomic functions of the body such as bladder control or blood pressure...
. These disorders are known as synucleinopathies. Alpha-synuclein is the primary structural component of Lewy body fibrils. Occasionally, Lewy bodies contain tau protein, however, alpha-synuclein and tau constitute two distinctive subsets of filaments in the same inclusion bodies. 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
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
that can be the precursor of aggregation and, ultimately, Lewy bodies. 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. The Epstein-Barr virus
Epstein-Barr virus
The Epstein–Barr virus , also called human herpesvirus 4 , is a virus of the herpes family and is one of the most common viruses in humans. It is best known as the cause of infectious mononucleosis...
has been implicated in these disorders.
In rare cases of familial forms of Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, there is a mutation in the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
coding for alpha-synuclein. Three point mutation
Point mutation
A point mutation, or single base substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA. Often the term point mutation also includes insertions or deletions of a single base pair...
s have been identified thus far: A53T, A30P and E46K. 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. 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
Intrinsically unstructured proteins
Intrinsically unstructured proteins, often referred to as naturally unfolded proteins or disordered proteins, are proteins characterized by lack of stable tertiary structure when the protein exists as an isolated polypeptide chain under physiological conditions in vitro...
but new evidence suggests that unmutated α-synuclein forms a stably folded tetramer
Tetramer
A tetramer is a protein with four subunits . There are homotetramers such as glutathione S-transferase or single-strand binding protein, dimers of hetero-dimers such as hemoglobin , and heterotetramers, where each subunit is different.-Subunit interactions in tetramers:The interactions between...
that resists aggregation
Protein aggregation
Protein aggregation is the aggregation of mis-folded proteins, and is thought to be responsible for many degenerative diseases, such as Alzheimer's. It has also been implicated in CAG repeat diseases....
.
Antibodies against alpha-synuclein have replaced antibodies against ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
as the gold standard for immunostaining
Immunostaining
Immunostaining is a general term in biochemistry that applies to any use of an antibody-based method to detect a specific protein in a sample. The term immunostaining was originally used to refer to the immunohistochemical staining of tissue sections, as first described by Albert Coons in 1941...
of Lewy bodies.
Certain sections of the alpha-synuclein protein may play a role in the tauopathies.
Protein-protein interactions
Alpha-synuclein has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with
- Dopamine transporterDopamine transporterThe dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
, - Parkin (ligase)Parkin (ligase)Parkin is a protein which in humans is encoded by the PARK2 gene. The precise function of this protein is unknown; however, the protein is a component of a multiprotein E3 ubiquitin ligase complex which in turn is part of the ubiquitin-proteasome system that mediates the targeting of proteins for...
, - Phospholipase D1Phospholipase D1Phospholipase D1 is an enzyme that in humans is encoded by the PLD1 gene.-Interactions:Phospholipase D1 has been shown to interact with RALA, BIN1, Amphiphysin, Alpha-synuclein, PEA15, RHOA, Protein kinase N1 and CDC42.-Inhibitors:...
, - SNCAIPSNCAIPSynphilin-1 is a protein that in humans is encoded by the SNCAIP gene.-Interactions:SNCAIP has been shown to interact with Alpha-synuclein and Parkin .-Further reading:...
, - Tau proteinTau proteinTau proteins are proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes...
.
See also
- SynucleinSynucleinSynucleins are a family of soluble proteins common to vertebrates, primarily expressed in neural tissue and in certain tumors.- Family members :The synuclein family includes three known proteins: alpha-synuclein, beta-synuclein, and gamma-synuclein...
- Contursi TermeContursi TermeContursi Terme is a village and comune in the province of Salerno in the Campania region of south-western Italy.-Early history:No secure identification of Contursi Terme, where ancient remains confirm a settlement at the confluence of the Tanagro with the Sele, is likely...
- the village in Italy where a mutation in the α-synuclein gene led to a family history of Parkinson's disease