<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SNCA — Alpha-Synuclein</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>SNCA</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Synuclein Alpha</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>4q22.1</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/6622" target="_blank">6622</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000145335" target="_blank">ENSG00000145335</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/163890" target="_blank">163890</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P37840" target="_blank">P37840</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td><a href="/diseases/parkinsons-disease">Parkinson's Disease</a>, <a href="/diseases/dementia-with-lewy-bodies">Dementia with Lewy Bodies</a>, <a href="/diseases/multiple-system-atrophy">Multiple System Atrophy</a></td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Substantia nigra, Cerebral cortex, Presynaptic terminals</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Mutations</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">A53T, A30P, E46K, H50Q, G51D</td>
</tr>
</table>
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SNCA — Alpha-Synuclein</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>SNCA</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Synuclein Alpha</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>4q22.1</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/6622" target="_blank">6622</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000145335" target="_blank">ENSG00000145335</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/163890" target="_blank">163890</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P37840" target="_blank">P37840</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td><a href="/diseases/parkinsons-disease">Parkinson's Disease</a>, <a href="/diseases/dementia-with-lewy-bodies">Dementia with Lewy Bodies</a>, <a href="/diseases/multiple-system-atrophy">Multiple System Atrophy</a></td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Substantia nigra, Cerebral cortex, Presynaptic terminals</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Mutations</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">A53T, A30P, E46K, H50Q, G51D</td>
</tr>
</table>
SNCA (Synuclein Alpha) is a gene located on chromosome 4q22.1 that encodes the alpha-synuclein (α-Syn) protein — the central pathological player in Parkinson's disease and related synucleinopathies. Discovered in 1997 when the A53T mutation was identified in the Contursi kindred[@mutation1997], SNCA is now recognized as the gene whose protein product forms the hallmark [Lewy bodies](/mechanisms/lewy-body-formation) found in [Parkinson's disease](/diseases/parkinsons-disease), [Dementia with Lewy Bodies](/diseases/dementia-with-lewy-bodies), and [Multiple System Atrophy](/diseases/multiple-system-atrophy)[@alphasynuclein1997].
SNCA is one of the most extensively studied genes in neurodegeneration research. Its discovery transformed our understanding of Parkinson's disease pathogenesis, establishing α-synuclein aggregation as the unifying mechanism across both familial and sporadic forms of the disease. The gene encodes a 140-amino acid protein that is predominantly expressed in presynaptic terminals of [neurons](/entities/neurons) throughout the brain, particularly in dopaminergic neurons of the [substantia nigra pars compacta](/cell-types/dopaminergic-neurons)[@physiological2019].
The SNCA gene spans approximately 417 kb on chromosome 4 at position 4q22.1. It consists of 6 exons, with the coding sequence distributed across exons 3-6. The gene structure is compact relative to its regulatory complexity, with extensive upstream and intronic regulatory elements influencing expression.
Multiple SNCA transcript variants have been identified:
The SNCA promoter contains binding sites for numerous transcription factors:
The α-synuclein protein consists of three distinct structural regions[@membrane2020]:
N-terminal Region (residues 1-60): Adopts an amphipathic alpha-helical conformation upon binding to lipid membranes. Contains 7 imperfect KTKEGV repeat motifs that mediate lipid interaction and membrane curvature sensing. This region is highly conserved across species and contains all known pathogenic mutations (A30P, E46K, A53T, G51D, H50Q).
NAC Domain (residues 61-95): The Non-Amyloid Component (NAC) is hydrophobic and central to aggregation propensity. Residues 71-82 form the core of the beta-sheet structure in amyloid fibrils. This domain is absent in some splice variants, and its length correlates with aggregation tendency.
C-terminal Region (residues 96-140): Highly acidic and unstructured in solution. The C-terminus mediates protein-protein interactions, chaperone activity, and regulatory post-translational modifications including phosphorylation at Ser129 — the major pathological modification found in >90% of Lewy body pathology[@phosphorylation2021].
α-Synuclein exists in multiple conformational states[@membrane2020]:
Cryo-EM studies have revealed distinct fibril conformations in different synucleinopathies, with [MSA fibrils showing different structures from PD/DLB](/diseases/multiple-system-atrophy) fibrils, supporting the "strain" hypothesis[@alphasynuclein2019a].
α-Synuclein is predominantly expressed in presynaptic terminals, comprising up to 1% of total cytosolic protein[@physiological2019]. Under normal physiological conditions:
High expression in:
The central pathogenic event in synucleinopathies is the misfolding and aggregation of α-Syn[@alphasynuclein2019]:
Post-translational modifications influencing aggregation include phosphorylation at Ser129, ubiquitination, truncation, and oxidation[@phosphorylation2021].
A critical breakthrough in understanding PD progression is the discovery that α-Syn propagates between neurons in a prion-like manner[@prionlike2014]:
α-Syn aggregates cause neuronal death through[@mitochondrial2014][@neuroinflammation2017]:
SNCA was the first gene linked to familial PD (Contursi kindred, A53T mutation, 1997)[@mutation1997]:
Characterized by diffuse [Lewy body](/mechanisms/lewy-body-formation) pathology with cortical and limbic involvement. SNCA mutations/duplications contribute to DLB pathogenesis.
Features predominantly oligodendroglial inclusions (GCIs) containing α-Syn fibrils with distinct strain properties from PD/DLB, suggesting different fibril conformations determine cell-type vulnerability[@alphasynuclein2019a].
| Mutation | Location | Effect |
|----------|----------|--------|
| A53T | Residue 53 | Enhanced aggregation, earlier onset (~46 years) |
| A30P | Residue 30 | Reduced membrane binding, enhanced oligomerization |
| E46K | Residue 46 | Increased aggregation, Lewy body formation |
| H50Q | Residue 50 | Moderate aggregation risk, later onset |
| G51D | Residue 51 | Reduced neuronal viability, earlier onset |
Gene duplications and triplications cause autosomal dominant PD with dose-dependent severity[@snca2013]. Even wild-type α-Syn overexpression is sufficient to cause neurodegeneration — aggregation is dose-dependent.
The NACP-REP1 microsatellite polymorphism (upstream of transcription start site) affects transcriptional activity. The 263bp allele increases PD risk ~1.5-2x, while the 261bp allele shows protective effects.
Synaptic Proteins: Synapsin I, synaptophysin, VAMP2 (regulates SNCA phase separation), CSPalpha.
Chaperones: Hsp70, Hsp90, Hsp40/DNAJB6, CHIP/STUB1 (E3 ubiquitin ligase for degradation).
Trafficking Proteins: Rab proteins (Rab3, Rab5, Rab8), NSF, complexin.
Membrane Receptors: PrPC (receptor for extracellular α-Syn), transferrin receptor (mediates uptake), LRP1.
Kinases and Phosphatases: LRRK2 (phosphorylates Ser129), GSK3-beta, casein kinases.
| Interactor | Role | Effect on Pathology |
|-----------|------|---------------------|
| [LRRK2](/entities/lrrk2) | Kinase | Phosphorylates alpha-syn at Ser129, accelerating aggregation |
| [GBA1](/genes/gba1) | Lysosomal enzyme | Deficiency increases glucosylceramide, promotes aggregation |
| [Parkin](/genes/park2) | E3 ligase | Ubiquitinates alpha-syn for degradation |
| TMEM106B | Lysosomal protein | Deficiency exacerbates aggregation (2026)[@tmemb2026] |
| VAMP2 | SNARE protein | Regulates phase separation of alpha-syn[@proteinprotein2024] |
| Fibrinogen | Coagulation factor | Exacerbates aggregation via alpha5beta3 integrin (2026)[@fibrinogen2026] |
SNCA is a major therapeutic target for disease modification in synucleinopathies[@alphasynucleintargeting2021]:
SNCA-related biomarkers are critical for diagnosis and clinical trials[@biological2024][@neuronally2024]:
Multiple clinical trials are targeting α-synuclein[@alphasynucleintargeting2021][@immunotherapy2021]:
| Agent | Company | Mechanism | Phase |
|-------|---------|-----------|-------|
| Cinamerene (BIIB054) | Biogen | Passive antibody | Phase 2 |
| UB-312 | UCB | Oligomer-targeting antibody | Phase 1 |
| REGN-PGN9 | Regeneron | Monoclonal antibody | Phase 1 |
| PR001A/PDA03A | AFFiRiS | Active immunotherapy | Phase 1 |
| Anle138b | MODAG | Aggregation inhibitor | Phase 1/2 |
| DNL310 | Denali | ASO therapy | Phase 1/2 |