Alpha-synuclein (aSyn) is a protein that, in humans, is encoded by the SNCA gene.

It is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release.

It is abundant in the brain, while smaller amounts are found in the heart, muscle and other tissues. 

In the brain, alpha-synuclein is found mainly in the axon terminals of presynaptic neurons.

In the axon terminals alpha-synuclein interacts with phospholipids and proteins.

These presynaptic terminals release neurotransmitters, from compartments known as synaptic vesicles. 

The neurotransmitters relay signals between neurons and is critical for normal brain function.

In Parkinson’s disease and other synucleinopathies, insoluble forms of alpha-synuclein accumulate as inclusions in Lewy bodies.

Familial Parkinson’s disease is associated with mutations in the synuclein (SNCA) gene. 

The alpha-synuclein protein is made of 140 amino acids.

Alpha-synuclein is a synuclein protein of unknown function.

 Alpha-synuclein is primarily found in neural tissue, making up as much as one percent of all proteins in the cytosol of brain cells.

Alpha-synuclein is expressed highly in neurons within the frontal cortex, hippocampus, striatum, and olfactory bulb.

Alpha-synuclein can also be found in the non-neuronal glial cells.

Alpha-synuclein is extensively localized in the nucleus of brain neurons.

Synuclein is however found predominantly in the presynaptic termini.

15% of synuclein being membrane-bound at any moment in neurons,

It is localized in neuronal mitochondria and highly expressed in the olfactory bulb, hippocampus, striatum and thalamus, where the cytosolic alpha-synuclein is also rich. 

The cerebral cortex and cerebellum are exceptions, which contain rich cytosolic alpha-synuclein but very low levels of mitochondrial alpha-synuclein. 

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.

Individuals diagnosed with various synucleinopathies often display constipation and other GI dysfunctions years prior to the onset of movement dysfunction. 

Alpha synuclein potentially connects the gut-brain axis in Parkinson’s disease patients. 

Common inherited Parkinson disease is associated with mutations in the alpha-synuclein (SNCA) gene. 

Alpha-synuclein acquires a cross-sheet structure similar to other amyloids. 

The Enterobacteriaceae in the human gut, can create curli, which are functional amyloid proteins. 

The unfolded amyloid CsgA, which is secreted by bacteria and later aggregates extracellularly to create biofilms, mediates adherence to epithelial cells, and aids in bacteriophage defense, forms the curli fibers. 

A hypothesis exists that aSyn disease in PD occurs via a gut-brain pathway. 

Intestinal dysbiosis may be a major factor in the development of Parkinson’s disease by encouraging intestinal permeability, gastrointestinal inflammation, and the aggregation and spread of aSyn.

The CNS and other peripheral tissues, such as the GIT, have physiological aSyn expression as well as its phosphorylated variants.

While the GI tract has been linked to other neurological disorders such autism spectrum disorder, depression, anxiety, and Alzheimer’s disease, protein aggregation and/or inflammation in the gut represents synucleinopathies.

Alpha-synuclein in solution is considered to be an intrinsically disordered protein, lacking a single stable 3D structure.

Alpha-synuclein is specifically upregulated in a discrete population of presynaptic terminals of the brain during a period of acquisition-related synaptic rearrangement.

Alpha-synuclein significantly interacts with tubulin, and that alpha-synuclein may have activity as a potential microtubule-associated protein, like tau.

Alpha-synuclein functions as a molecular chaperone, and is involved in the functioning of the neuronal Golgi apparatus and vesicle trafficking.

Alpha-synuclein is essential for normal development of the cognitive functions.

Apha-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.

The binding of alpha-synuclein to lipid membranes alters the bilayer structure and leading to the formation of small vesicles.

Aggregated states of alpha-synuclein permeate the membrane of lipid vesicles.

Studies suggest that alpha synuclein plays a role in restricting the mobility of synaptic vesicles, consequently attenuating synaptic vesicle recycling and neurotransmitter release.

It may also help regulate the release of dopamine, a type of neurotransmitter that is critical for controlling the start and stop of voluntary and involuntary movements.

Alpha-synuclein modulates DNA repair processes, including repair of double-strand breaks (DSBs).

The DNA repair function of alpha-synuclein appears to be compromised in Lewy body inclusion bearing neurons, and this may trigger cell death.

In some neurodegenerative diseases, alpha-synuclein produces insoluble inclusion bodies: synucleinopathies

Synucleinopathies,  are connected with either higher levels of normal alpha-synuclein or its mutant variants.

Alpha-synuclein represents an effector for neural stem and progenitor cell activation.

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

Alpha synuclein, has no single, well-defined tertiary structure, is an intrinsically disordered protein.

Under certain pathological conditions, it can misfold in a way that exposes its core hydrophobic residues providing the opportunity for hydrophobic interactions to occur with a similar, equally exposed protein.

This could lead to subsequent aggregation into large, insoluble fibrils known as amyloids.

Alpha-synuclein aggregates 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.

Aggregation of alpha-synuclein may lead to various cellular disorders including microtubule impairment, synaptic and mitochondrial dysfunctions, oxidative stress as well as dysregulation of calcium signaling, proteasomal and lysosomal pathway.

Alpha-synuclein is the primary structural component of Lewy body fibrils. 

Lewy bodies rarely contain tau protein.

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.

The  strategy to treat synucleinopathies are compounds that inhibit aggregation of alpha-synuclein. 

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. 

A total of nineteen mutations in the SNCA gene have been associated with parkinsonism.

Some mutations of alpha-synuclein may cause it to form amyloid-like fibrils that contribute to Parkinson’s disease. 

Over-expression of human wild-type or mutant alpha-synuclein in drives deposition of alpha-synuclein in the ventral midbrain, degeneration of the dopaminergic system and impaired motor performance.

A prion form of the protein alpha-synuclein may be a causal agent for the disease multiple system atrophy.

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