SNCAIP

Synphilin-1 is a protein that in humans is encoded by the SNCAIP gene.^[5][6] SNCAIP stands for "synuclein, alpha interacting protein".

SNCAIP
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2KES
Identifiers
Aliases	SNCAIP, SYPH1, Sph1, synuclein alpha interacting protein
External IDs	OMIM: 603779; MGI: 1915097; HomoloGene: 3987; GeneCards: SNCAIP; OMA:SNCAIP - orthologs
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5q23.2 Start 122,311,354 bp[1] End 122,464,219 bp[1]
Gene location (Mouse) Chr. Chromosome 18 (mouse)[2] Band 18|18 D1 Start 52,900,781 bp[2] End 53,049,007 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in ventricular zone ganglionic eminence germinal epithelium periodontal fiber endometrium parietal pleura stromal cell of endometrium epithelium of bronchus bronchial epithelial cell myometrium Top expressed in genital tubercle ventricular zone ganglionic eminence lumbar subsegment of spinal cord external carotid artery saccule internal carotid artery neural tube Rostral migratory stream renal corpuscle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding ubiquitin protein ligase binding identical protein binding Cellular component cytoplasm cytosol soma presynaptic membrane synaptic vesicle nucleoplasm cytoplasmic ribonucleoprotein granule Biological process regulation of inclusion body assembly dopamine metabolic process cell death regulation of neurotransmitter secretion Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 9627 67847 Ensembl ENSG00000064692 ENSMUSG00000024534 UniProt Q9Y6H5 Q99ME3 RefSeq (mRNA) NM_001242935 NM_001308100 NM_001308105 NM_001308106 NM_001308107 NM_001308108 NM_001308109 NM_005460 NM_001199151 NM_001199153 NM_001199154 NM_026408 RefSeq (protein) NP_001229864 NP_001295029 NP_001295034 NP_001295035 NP_001295036 NP_001295037 NP_001295038 NP_005451 NP_001186080 NP_001186082 NP_001186083 NP_080684 NP_001390575 NP_001390576 NP_001390577 Location (UCSC) Chr 5: 122.31 – 122.46 Mb Chr 18: 52.9 – 53.05 Mb PubMed search [3] [4]
Wikidata
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Synphilin-1 is a cytosolic protein first identified in 1999 as a novel binding partner of α-synuclein, localized within Lewy bodies in Parkinson’s disease brain tissue.^[7] Experimental studies in mammalian cells and yeast demonstrated that co-expression of synphilin-1 with α-synuclein promotes the formation of cytoplasmic inclusions resembling Lewy bodies.^[7]

Structure

The SNCAIP gene encodes synphilin-1, a multi-domain protein with a complex structure integral to neuronal function and implicated in neurodegenerative diseases. Structurally, synphilin-1 is composed of approximately 919 amino acids and is characterized by several functional domains, notably including six ankyrin repeats and a central coiled-coil domain spanning residues 510–557. These domains are typical protein-protein interaction motifs, facilitating synphilin-1's ability to interact with partner proteins such as alpha-synuclein (SNCA). SNCAIP binds to the N-terminal region of SNCA, allowing synphilin-1 to play a role in the formation of cytosolic inclusions mimicking Lewy bodies, which are hallmark features of synucleinopathies. The ankyrin repeats provide scaffolding for additional protein interactions, while the coiled-coil domain is crucial for the association with alpha-synuclein and possibly other synaptic or vesicular components.^[8][9]

Function

SNCAIP encodes synphilin-1, a cytoplasmic protein that interacts with alpha-synuclein in neuronal tissue and is involved in a variety of physiological processes related to synaptic function and protein homeostasis. Synphilin-1 is developmentally localized to synaptic terminals and participates in the regulation of synaptic vesicle trafficking. It may act as a scaffold protein, contributing to cellular processes like protein degradation through the ubiquitin-proteasome system and autophagy. Experimental evidence suggests that binding of synphilin-1 to alpha-synuclein can modulate synaptic vesicle dynamics, potentially impacting neurotransmitter release and synaptic plasticity. Synphilin-1’s cytoprotective effects include inhibiting mitochondrial dysfunction, reducing reactive oxygen species production, and promoting neuronal survival under certain conditions.^{[10][11][12][13]}

Ubiquitination

Synphilin-1 undergoes ubiquitination. Parkin (an E3 ligase) modifies synphilin-1 and, together with α-synuclein, promotes the formation of ubiquitin-positive inclusion bodies.^[14] Mutations in parkin gene disrupt this activity. Additional E3 ligases, including SIAH1 and SIAH2, also ubiquitinate synphilin-1, influencing whether the protein is directed to proteasomal degradation or accumulates in inclusions.^[15] Inclusions containing α-synuclein and synphilin-1 share features with aggresomes, which may act to sequester misfolded proteins and limit cellular toxicity.^[16]

Clinical significance

Clinically, synphilin-1 is heavily implicated in neurodegenerative diseases, particularly Parkinson’s disease (PD). It serves as a major component of Lewy bodies—the pathological protein aggregates characteristic of PD—and contributes to the formation of these cytoplasmic inclusions. While wild-type synphilin-1 may help sequester potentially toxic protein aggregates, certain isoforms and mutants, such as synphilin-1A, are highly aggregation-prone and associated with neuronal toxicity and degeneration. Genetic variation and altered methylation of the SNCAIP gene are linked with increased vulnerability to PD and related synucleinopathies. Thus, synphilin-1 exerts complex effects on neuronal health, acting as both a potential protector and a contributor to disease pathology depending on its expression, isoform, and interaction context.^{[17][18][13][19]}

Beyond Parkinson’s disease, synphilin-1 has recently been implicated in glioblastoma. Transcriptomic and single-cell RNA sequencing analyses identified SNCAIP among histone lactylation related genes upregulated in glioblastoma, with elevated expression correlating with poorer patient survival.^[20] This has raised interest in synphilin-1 as a potential biomarker in cancer biology.

Interactions

SNCAIP has been shown to interact with:

• Alpha-synuclein^{[5][21][22][23]} and
• Parkin (ligase).^[24]