SNCAIP

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
View/Edit Human View/Edit Mouse

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

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]

References

1. GRCh38: Ensembl release 89: ENSG00000064692 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000024534 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Engelender S, Kaminsky Z, Guo X, Sharp AH, Amaravi RK, Kleiderlein JJ, et al. (May 1999). "Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions". Nat Genet. 22 (1): 110–114. doi:10.1038/8820. PMID 10319874. S2CID 2611127.
6. "Entrez Gene: SNCAIP synuclein, alpha interacting protein (synphilin)".
7. Engelender S, Kaminsky Z, Guo X, Sharp AH, Amaravi RK, Kleiderlein JJ, et al. (May 1999). "Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions". Nature Genetics. 22 (1): 110–114. doi:10.1038/8820. PMID 10319874.
8. Siddiqui IJ, Pervaiz N, Abbasi AA (April 2016). "The Parkinson Disease gene SNCA: Evolutionary and structural insights with pathological implication". Scientific Reports. 6 24475. Bibcode:2016NatSR...624475S. doi:10.1038/srep24475. PMC 4832246. PMID 27080380.
9. "SNCAP_HUMAN". UniProt. Q9Y6H5.
10. Ribeiro CS, Carneiro K, Ross CA, Menezes JR, Engelender S (Jun 2002). "Synphilin-1 is developmentally localized to synaptic terminals, and its association with synaptic vesicles is modulated by alpha-synuclein". Journal of Biological Chemistry. 277 (26): 23927–23933. doi:10.1074/jbc.M201115200. PMID 11956199.
11. Krüger R (Oct 2004). "The role of synphilin-1 in synaptic function and protein degradation". Cell Tissue Res. 318 (1): 195–199. doi:10.1007/s00441-004-0953-z. PMID 15322916. S2CID 12186058.
12. Mirghani M. Synphilin-1 and its Effects on Pathogenesis of Parkinson's Synphilin-1 and its Effects on Pathogenesis of Parkinson's Disease (B.S. thesis). University of Connecticut.
13. Shishido T, Nagano Y, Araki M, Kurashige T, Obayashi H, Nakamura T, et al. (January 2019). "Synphilin-1 has neuroprotective effects on MPP+-induced Parkinson's disease model cells by inhibiting ROS production and apoptosis". Neuroscience Letters. 690: 145–150. doi:10.1016/j.neulet.2018.10.020. PMID 30316984.
14. Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, et al. (October 2001). "Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease". Nature Medicine. 7 (10): 1144–1150. doi:10.1038/nm1001-1144. PMID 11590439.
15. Liani E, Eyal A, Avraham E, Shemer R, Szargel R, Berg D, et al. (April 2004). "Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson's disease". Proceedings of the National Academy of Sciences of the United States of America. 101 (15): 5500–5505. Bibcode:2004PNAS..101.5500L. doi:10.1073/pnas.0401081101. PMC 397412. PMID 15064394.
16. Tanaka M, Kim YM, Lee G, Junn E, Iwatsubo T, Mouradian MM (February 2004). "Aggresomes formed by alpha-synuclein and synphilin-1 are cytoprotective". The Journal of Biological Chemistry. 279 (6): 4625–4631. doi:10.1074/jbc.M310994200. PMID 14627698.
17. Eyal A, Szargel R, Avraham E, Liani E, Haskin J, Rott R, et al. (April 2006). "Synphilin-1A: an aggregation-prone isoform of synphilin-1 that causes neuronal death and is present in aggregates from alpha-synucleinopathy patients". Proceedings of the National Academy of Sciences of the United States of America. 103 (15): 5917–22. Bibcode:2006PNAS..103.5917E. doi:10.1073/pnas.0509707103. PMC 1458673. PMID 16595633.
18. Carvajal-Oliveros A, Dominguez-Baleón C, Sánchez-Díaz I, Zambrano-Tipan D, Hernández-Vargas R, Campusano JM, et al. (2023). "Parkinsonian phenotypes induced by Synphilin-1 expression are differentially contributed by serotonergic and dopaminergic circuits and suppressed by nicotine treatment". PLOS ONE. 18 (3) e0282348. Bibcode:2023PLoSO..1882348C. doi:10.1371/journal.pone.0282348. PMC 9977059. PMID 36857384.
19. Dashtipour K, Tafreshi A, Adler C, Beach T, Chen X, Serrano G, et al. (June 2017). "Hypermethylation of Synphilin-1, Alpha-Synuclein-Interacting Protein (SNCAIP) Gene in the Cerebral Cortex of Patients with Sporadic Parkinson's Disease". Brain Sciences. 7 (7): 74. doi:10.3390/brainsci7070074. PMC 5532587. PMID 28653979.
20. He W, Chen R, Chen G, Zhang L, Qian Y, Zhou J, et al. (2025). "Identification and Validation of Prognostic Genes Related to Histone Lactylation Modification in Glioblastoma: An Integrated Analysis of Transcriptome and Single-cell RNA Sequencing". Journal of Cancer. 16 (7): 2145–2166. doi:10.7150/jca.110646. PMC 12036088. PMID 40302809.
21. Neystat M, Rzhetskaya M, Kholodilov N, Burke RE (June 2002). "Analysis of synphilin-1 and synuclein interactions by yeast two-hybrid beta-galactosidase liquid assay". Neurosci. Lett. 325 (2): 119–123. doi:10.1016/s0304-3940(02)00253-7. PMID 12044636. S2CID 11517781.
22. Nagano Y, Yamashita H, Nakamura T, Takahashi T, Kondo E, Nakamura S (Dec 2001). "Lack of binding observed between human alpha-synuclein and Bcl-2 protein family". Neurosci. Lett. 316 (2): 103–107. doi:10.1016/s0304-3940(01)02330-8. PMID 11742726. S2CID 54363210.
23. Kawamata H, McLean PJ, Sharma N, Hyman BT (May 2001). "Interaction of alpha-synuclein and synphilin-1: effect of Parkinson's disease-associated mutations". J. Neurochem. 77 (3): 929–934. doi:10.1046/j.1471-4159.2001.00301.x. PMID 11331421. S2CID 83885937.
24. Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, et al. (October 2001). "Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease". Nat. Med. 7 (10): 1144–1150. doi:10.1038/nm1001-1144. PMID 11590439. S2CID 12487644.

Further reading

• Engelender S, Wanner T, Kleiderlein JJ, Wakabayashi K, Tsuji S, Takahashi H, et al. (Sep 2000). "Organization of the human synphilin-1 gene, a candidate for Parkinson's disease". Mamm. Genome. 11 (9): 763–766. doi:10.1007/s003350010123. PMID 10967135. S2CID 22420090.
• Kawamata H, McLean PJ, Sharma N, Hyman BT (May 2001). "Interaction of alpha-synuclein and synphilin-1: effect of Parkinson's disease-associated mutations". J. Neurochem. 77 (3): 929–934. doi:10.1046/j.1471-4159.2001.00301.x. PMID 11331421. S2CID 83885937.
• Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, et al. (Oct 2001). "Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease". Nat. Med. 7 (10): 1144–1150. doi:10.1038/nm1001-1144. PMID 11590439. S2CID 12487644.
• O'Farrell C, Pickford F, Vink L, McGowan E, Cookson MR (Mar 2002). "Sequence conservation between mouse and human synphilin-1". Neurosci. Lett. 322 (1): 9–12. doi:10.1016/S0304-3940(02)00068-X. PMID 11958831. S2CID 9654263.
• Neystat M, Rzhetskaya M, Kholodilov N, Burke RE (Jun 2002). "Analysis of synphilin-1 and synuclein interactions by yeast two-hybrid beta-galactosidase liquid assay". Neurosci. Lett. 325 (2): 119–123. doi:10.1016/S0304-3940(02)00253-7. PMID 12044636. S2CID 11517781.
• Junn E, Lee SS, Suhr UT, Mouradian MM (Dec 2002). "Parkin accumulation in aggresomes due to proteasome impairment". Journal of Biological Chemistry. 277 (49): 47870–47877. doi:10.1074/jbc.M203159200. PMID 12364339.
• Ihara M, Tomimoto H, Kitayama H, Morioka Y, Akiguchi I, Shibasaki H, et al. (Jun 2003). "Association of the cytoskeletal GTP-binding protein Sept4/H5 with cytoplasmic inclusions found in Parkinson's disease and other synucleinopathies". Journal of Biological Chemistry. 278 (26): 24095–24102. doi:10.1074/jbc.M301352200. PMID 12695511.
• Ito T, Niwa J, Hishikawa N, Ishigaki S, Doyu M, Sobue G (Aug 2003). "Dorfin localizes to Lewy bodies and ubiquitylates synphilin-1". Journal of Biological Chemistry. 278 (31): 29106–29114. doi:10.1074/jbc.M302763200. PMID 12750386.
• Marx FP, Holzmann C, Strauss KM, Li L, Eberhardt O, Gerhardt E, et al. (Jun 2003). "Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease". Hum. Mol. Genet. 12 (11): 1223–1231. doi:10.1093/hmg/ddg134. PMID 12761037.
• Scherzer CR, Jensen RV, Gullans SR, Feany MB (Oct 2003). "Gene expression changes presage neurodegeneration in a Drosophila model of Parkinson's disease". Hum. Mol. Genet. 12 (19): 2457–2466. doi:10.1093/hmg/ddg265. PMID 12915459.
• Nagano Y, Yamashita H, Takahashi T, Kishida S, Nakamura T, Iseki E, et al. (Dec 2003). "Siah-1 facilitates ubiquitination and degradation of synphilin-1". Journal of Biological Chemistry. 278 (51): 51504–51514. doi:10.1074/jbc.M306347200. PMID 14506261.
• Tanaka M, Kim YM, Lee G, Junn E, Iwatsubo T, Mouradian MM (Feb 2004). "Aggresomes formed by alpha-synuclein and synphilin-1 are cytoprotective". Journal of Biological Chemistry. 279 (6): 4625–4631. doi:10.1074/jbc.M310994200. PMID 14627698.
• Lee G, Tanaka M, Park K, Lee SS, Kim YM, Junn E, et al. (Feb 2004). "Casein kinase II-mediated phosphorylation regulates alpha-synuclein/synphilin-1 interaction and inclusion body formation". Journal of Biological Chemistry. 279 (8): 6834–6839. doi:10.1074/jbc.M312760200. PMID 14645218.
• Chung KK, Thomas B, Li X, Pletnikova O, Troncoso JC, Marsh L, et al. (May 2004). "S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function". Science. 304 (5675): 1328–1331. Bibcode:2004Sci...304.1328C. doi:10.1126/science.1093891. PMID 15105460. S2CID 86854030.