SNCA

Official Full Name

synuclein alpha

Organism

Homo sapiens

GeneID

6622

Background

Alpha-synuclein is a member of the synuclein family, which also includes beta- and gamma-synuclein. Synucleins are abundantly expressed in the brain and alpha- and beta-synuclein inhibit phospholipase D2 selectively. SNCA may serve to integrate presynaptic signaling and membrane trafficking. Defects in SNCA have been implicated in the pathogenesis of Parkinson disease. SNCA peptides are a major component of amyloid plaques in the brains of patients with Alzheimer's disease. Alternatively spliced transcripts encoding different isoforms have been identified for this gene. [provided by RefSeq, Feb 2016]

Synonyms

PD1; NACP; PARK1; PARK4;

Bio Chemical Class

Synuclein

Protein Sequence

MDVFMKGLSKAKEGVVAAAEKTKQGVAEAAGKTKEGVLYVGSKTKEGVVHGVATVAEKTKEQVTNVGGAVVTGVTAVAQKTVEGAGSIAAATGFVKKDQLGKNEEGAPQEGILEDMPVDPDNEAYEMPSEEGYQDYEPEA

Open

Disease

Alzheimer disease, Autonomic nervous system disorder, Parkinsonism

Approved Drug

Clinical Trial Drug

11 +

Discontinued Drug

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Detailed Information

Mostly found at presynaptic terminals of neurons, α-syn is essential for synaptic vesicle exocytosis. Serving as a monomer, it enhances the dilatation of exocytotic fusion pores, vesicle priming, and fusion. Mechanistically, α-syn facilitates the release from microdomains of local calcium ions (Ca²), hence promoting ATP-induced exocytosis. It also functions as a molecular chaperone, guiding SNARE proteins—very important for the release of neurotransmitters—to fold properly. Two functional zones define α-syn's structure: the C-terminal and N-terminal zones. Seen in the N-terminal region, an amphipathic alpha-helical motif allows α-syn to bind to phospholipids and facilitates protein-protein interactions. By contrast, the less organized C-terminal region reduces interactions with other cytosolic or membrane-bound proteins.

The SNCA Gene and Its Isoforms

Parkinson's disease is the second most typically occurring neurological disease after Alzheimer's disease. Non-motor symptoms include constipation, orthostatic hypotension, rapid eye movement behavior disorder, apathy, and dementia; motor symptoms include tremors, stiffness, bradykinesia, and PD-defined postural instability. Rich in α-syn aggregates, Lewy bodies characterize the pathogenic element of Parkinson's disease.

Given its pathophysiology, α-syn is now a potential biomarker for Parkinson's disease. Particularly certain SNCA gene mutations, such as A53T and A30P, cause an accumulation of α-syn, which clarifies the neurodegenerative processes seen in Parkinson's disease. Genome-wide association studies have shown variations in the SNCA gene as PD risk factors, thereby underlining the importance of genetic predisposition in the emergence of illnesses.

Figure 1 explains the process of α-synuclein aggregation, detailing how monomers transition to oligomers and ultimately to fibrils when the balance between production and clearance is disrupted. Figure 1. The process of α-synuclein aggregation. (Du XY, et al., 2020)

Parkinson's Disease and Alpha-Synuclein

Particularly phosphorylation and post-translational modifications (PTMs) of α-syn have drawn great attention because of their ramifications for neurotoxicity. About 90% of insoluble α-syn within Lewy bodies is phosphorylated, predominantly at Ser-129, a shift tightly related to neurotoxic effects. Phosphorylation increases the aggregation propensity of α-syn, therefore disturbing the delicate balance between protein synthesis and breakdown. Under pathogenic conditions, the physiological function of α-syn as a chaperone in SNARE complex formation is disrupted, which reduces synaptic activity and finally contributes to producing neurodegeneration.

Apart from phosphorylation, various variables may affect α-syn structure and aggregation including oxidative stress, protein breakdown pathways, and lipid content. For instance, oxidative stress facilitates the development of harmful oligomers, which could induce neurotoxicity via many pathways including endoplasmic reticulum (ER) stress, synaptic damage, and mitochondrial failure.

Mechanisms of Neurotoxicity

The neurotoxicity of α-syn oligomers has been associated with many related mechanisms. α-syn accumulation first causes mitochondrial dysfunction, largely influencing the function of mitochondrial complex I. Oxidative stress brought on by this disturbance of ATP synthesis eventually causes neuronal death. Furthermore, α-syn oligomers might induce ER stress, hence setting off a vicious cycle aggravating the buildup of toxic α-syn species.

Maintaining protein homeostasis within cells mostly relies on the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway. But when these degradation pathways are overwhelmed—as they are in PD—they may assist in accumulating misfolded proteins such as α-syn. Soluble α-syn oligomers can prohibit the proteasome from operating, therefore preventing the breakdown of other cellular substrates and so prolonging the cycle of protein aggregation.

Normal physiological function in the synaptic environment depends on α-syn, which is maintained by interactions with SNARE proteins. Higher degrees of α-syn oligomers, however, might interfere with synaptic vesicle recycling and lower neurotransmission, hence generating synaptic degeneration and loss. Changes in axonal transport and diminishing synaptic vesicle density help to explain the pathogenesis of Parkinson's disease, therefore highlighting the complicated role of α-syn in synaptic health.

Inflammatory Responses and Alpha-Synuclein

Particularly in astrocytes and microglia, new evidence suggests that α-syn oligomers affect glial cell activity in addition to neurons. Astrocytes may absorb α-syn expelled from neurons, triggering an inflammatory response characterized by the generation of pro-inflammatory cytokines. Microglial cells may also detect α-syn oligomers via toll-like receptors (TLRs), therefore triggering inflammatory processes and aggravating neuronal damage even further.

Released in response to α-syn aggregates, inflammatory cytokines including TNF-α could induce neurotoxicity and support neurodegeneration forward. The relationship between α-syn and glial cells highlights the importance of neuroinflammation in the pathogenesis of Parkinson's disease and suggests that focusing on inflammatory pathways could provide therapy methods.

References:

Atik A, Stewart T, Zhang J. Alpha-Synuclein as a Biomarker for Parkinson's Disease. Brain Pathol. 2016;26(3):410-418.
Chen M, Mor DE. Gut-to-Brain α-Synuclein Transmission in Parkinson's Disease: Evidence for Prion-like Mechanisms. Int J Mol Sci. 2023;24(8):7205.
Du XY, Xie XX, Liu RT. The Role of α-Synuclein Oligomers in Parkinson's Disease. Int J Mol Sci. 2020;21(22):8645.
Kawahata I, Finkelstein DI, Fukunaga K. Pathogenic Impact of α-Synuclein Phosphorylation and Its Kinases in α-Synucleinopathies. Int J Mol Sci. 2022;23(11):6216.
Tofaris GK. Initiation and progression of α-synuclein pathology in Parkinson's disease. Cell Mol Life Sci. 2022;79(4):210.

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