SNCA
Synuclein alpha
Gene Number: 6622
Location: 4q22.1
Key Functions: Synaptic function regulation, neurotransmitter release, neuronal plasticity, protein homeostasis, and neurodegeneration prevention
SNCA encodes alpha-synuclein, a small presynaptic neuronal protein that plays a central role in the regulation of synaptic vesicle trafficking, neurotransmitter release, and synaptic plasticity. Under physiological conditions, alpha-synuclein associates with synaptic vesicle membranes and modulates the assembly of SNARE complexes, facilitating the efficient fusion of vesicles and the release of neurotransmitters such as dopamine. It is particularly abundant in dopaminergic neurons of the substantia nigra, highlighting its importance in fine-tuning neuronal signaling and maintaining normal motor and cognitive function.
Structurally, alpha-synuclein is characterized by its intrinsically disordered conformation, allowing it to dynamically interact with lipids, membranes, and proteins within the presynaptic terminal. In its native, soluble form, it supports synaptic vesicle recycling, neuronal adaptability, and protection against oxidative stress. However, alterations in its folding or post-translational modifications—such as phosphorylation or nitration—can promote the transition from its monomeric state into oligomeric and fibrillar aggregates.
Pathologically, abnormal aggregation of alpha-synuclein into Lewy bodies and Lewy neurites is a hallmark of Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy—collectively termed synucleinopathies. These aggregates disrupt intracellular trafficking, impair mitochondrial function, and trigger neuroinflammatory responses, leading to progressive neuronal loss.
Mutations or multiplications in SNCA, such as A53T, A30P, E46K, and gene duplications/triplications, directly increase aggregation propensity and disease severity.
Beyond its neurodegenerative role, alpha-synuclein also participates in cellular stress regulation and lipid metabolism, suggesting that its physiological balance is crucial for neuronal resilience. Dysregulated expression or aggregation compromises synaptic integrity, energy metabolism, and proteostatic mechanisms, culminating in dopaminergic degeneration and motor dysfunction.
Because of its central role in the pathogenesis of Parkinson’s disease, SNCA remains a major target for disease-modifying therapeutic strategies, including approaches aimed at reducing alpha-synuclein expression, inhibiting aggregation, or enhancing its clearance via autophagy—representing one of the most active frontiers in neurodegenerative disease research.
SNP ID | Your Genotype | Alternative Alleles | Interpretation |
|---|---|---|---|
rs356219 | No matching variant or no valid DNA data | A | No interpretation available |
rs11931074 | No matching variant or no valid DNA data | T | No interpretation available |
rs356219
AA – Normal risk for Parkinson’s disease (PD) (R).
AG – ~1.3× increased risk of PD (R).
GG – ~1.6× increased risk of PD (R).
Functional effect: The G allele is linked to higher SNCA (α-synuclein) expression in the substantia nigra and cerebrocerebellar regions and raises PD risk, marking a key tagging SNP for a PD-associated haplotype.
rs11931074
GG – Normal risk for Parkinson’s disease (R).
GT – ~1.3–1.5× increased risk of PD (ethnicity-dependent) (R).
TT – ~1.3–1.4× increased risk of PD, particularly under a recessive model (R).
Functional effect: The T allele in the 3′ region of SNCA is associated with elevated PD susceptibility across multiple populations, likely through effects on α-synuclein expression. The risk magnitude varies by ethnicity and depends on genetic model.
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