Alternative titles; symbols
HGNC Approved Gene Symbol: SNCAIP
Cytogenetic location: 5q23.2 Genomic coordinates (GRCh38) : 5:122,311,353-122,464,219 (from NCBI)
To determine the protein interaction partners of alpha-synuclein (SNCA; 163890), mutations in which can cause Parkinson disease (168600), Engelender et al. (1999) screened human brain libraries in the yeast 2-hybrid system. They identified a novel interacting protein they designated synphilin-1, encoded by the gene SNCAIP. The predicted 919-amino acid synphilin-1 protein contains several protein-protein interaction domains, such as ankyrin-like repeats and a coiled-coil domain. An approximately 4-kb SNCAIP transcript was detected in many human tissues by Northern blot analysis and was particularly enriched in brain, heart, and placenta. Synphilin-1 was present in many regions in brain, including substantia nigra. In immunoblot analyses of human brain, synphilin-1 appeared as a single band of approximately 90 kD in several brain regions, with no differences in the level of expression in controls, patients with PD, or patients with Alzheimer disease (104300). They found that alpha-synuclein interacts in vivo with synphilin-1 in neurons. Cotransfection of both proteins (but not control proteins) in HEK293 cells yielded cytoplasmic eosinophilic inclusions.
Using immunohistochemistry in human postmortem brain tissue, Engelender et al. (2000) found that synphilin-1 protein, like alpha-synuclein protein, is present in neuropil.
Eyal et al. (2006) cloned an alternatively spliced synphilin-1 isoform, termed synphilin-1A, that has a different start codon from synphilin-1, lacks exons 3 and 4, and contains a previously undescribed exon, termed 9A. The molecular mass of synphilin-1A is approximately 75 kD.
Engelender et al. (1999) determined that synphilin-1 interacts with alpha-synuclein.
Chung et al. (2001) showed that parkin (602544) interacts with and ubiquitinates synphilin-1. Coexpression of alpha-synuclein, synphilin-1, and parkin resulted in the formation of Lewy body-like ubiquitin-positive cytosolic inclusions. They further showed that familial mutations in parkin disrupt the ubiquitination of synphilin-1 and the formation of the ubiquitin-positive inclusions. Chung et al. (2001) concluded that their results provided a molecular basis for the ubiquitination of Lewy body-associated proteins and linked parkin and alpha-synuclein in a common pathogenic mechanism through their interaction with synphilin-1.
Marx et al. (2003) observed that transient transfection of human neuroblastoma cells with synphilin-1 resulted in the formation of 1 or more cytoplasmic inclusions in a subset of cells. Similar results were obtained with human embryonic kidney cells. When subjected to proteasomal inhibition with lactacystin, the number of transfected neuroblastoma cells with cytoplasmic synphilin-1 inclusions was increased, suggesting that synphilin-1 is physiologically degraded by the proteasome.
Eyal et al. (2006) showed that synphilin-1A binds to alpha-synuclein and induces the formation of intracellular aggregates in cultured human neuronal cells. Overexpression of synphilin-1A resulted in cellular toxicity that was attenuated by the formation of inclusions. Synphilin-1A was found in Lewy bodies of patients with Parkinson disease and Lewy body dementia (127750), suggesting a role in neuronal degeneration.
Tsai et al. (2012) showed that human kalirin (KALRN; 604605) isoform-7 promoted recruitment of perinuclear synphilin-1 inclusions into aggresomes in an HDAC6 (300272)-dependent manner and increased the susceptibility of synphilin-1 inclusions to degradation. Kalirin-7 and synphilin-1 interacted with each other, and both also interacted with HDAC6. All 3 proteins acted as a common complex and increased transportation of synphilin-1 into aggresomes through kalirin-mediated deacetylation of HDAC6.
Engelender et al. (2000) determined that the human SNCAIP gene contains 10 exons and has a highly polymorphic GT repeat within intron 5 that is suitable for linkage analysis in families with Parkinson disease. Eyal et al. (2006) identified an additional exon termed 9A in transcripts of synphilin-1A.
By radiation hybrid mapping, Engelender et al. (1999) showed that the SNCAIP gene is located on 5q23.1-q23.3.
Reclassified Variants
The R621C variant in the SNCAIP gene (603779.0001) as a cause of Parkinson disease has been reclassified as a variant of unknown significance. In 2 apparently sporadic patients with Parkinson disease, Marx et al. (2003) found an arg621-to-cys (R621C) mutation in synphilin-1 (603779.0001).
Nuber et al. (2010) generated transgenic mice overexpressing either wildtype human SNCAIP or human R621C-variant SNCAIP in brain and observed increased dopamine levels in the nigrostriatal system at age 3 months in both types. Neuropathologic examination showed ubiquitin-positive inclusions in cerebellar sections and degeneration of Purkinje cells, but not in the substantia nigra. Both transgenic mouse lines showed a significant reduction of motor skill learning and motor performance compared to controls, with R621C-variant mice performing weakest. These findings suggested a pathologic role for overexpression of synphilin-1 in vivo.
Using a mouse prion protein promoter, Smith et al. (2010) generated synphilin-1 transgenic mice, which did not display PD-like phenotypes. However, synphilin-1/A53T alpha-synuclein double-transgenic mice survived longer than A53T alpha-synuclein single-transgenic mice. There were attenuated A53T alpha-synuclein-induced motor abnormalities, decreased astroglial reaction, and neuronal degeneration in brains of double-transgenic mice. Overexpression of synphilin-1 decreased caspase-3 (CASP3; 600636) activation, increased beclin-1 (BECN1; 604378) and LC3 II (MAP1LC3A; 601242) expression, and promoted formation of aggresome-like structures, suggesting that synphilin-1 may alter multiple cellular pathways to protect against neuronal degeneration. The authors concluded that synphilin-1 can diminish the severity of alpha-synucleinopathy and may play a neuroprotective role against A53T alpha-synuclein toxicity in vivo.
This variant, formerly titled PARKINSON DISEASE based on the report of Marx et al. (2003), has been reclassified based on the findings of Myhre et al. (2008).
Marx et al. (2003) performed mutation analysis of the synphilin-1 gene in 328 German familial and sporadic Parkinson disease (PD; 168600) patients. In 2 apparently sporadic patients, the authors identified a 1861C-T transition in exon 9, leading to an arg621-to-cys (R621C; 603779.0001) substitution at a conserved residue. Both patients shared the same rare alleles in 5 flanking microsatellite markers. The mutation was absent in a total of 702 chromosomes from healthy German controls. The ability of mutant synphilin-1 to form cytoplasmic inclusions in transfected human neuroblastoma cells was reduced compared to wildtype, and when subjected to proteasomal inhibition, cells expressing R621C synphilin-1 showed a significantly reduced number of inclusions compared with cells expressing wildtype protein. R621C synphilin-1 transfected cells were more susceptible to staurosporine-induced cell death than cells expressing wildtype synphilin-1. Marx et al. (2003) speculated that the R621C mutation in synphilin-1 prevents its sequestration into intracytoplasmic aggregations and leads to an increased accumulation of toxic intermediates by defective ubiquitination and/or proteasomal inhibition. Marx et al. (2003) concluded that the R621C mutation in the synphilin-1 gene may play a causative role in Parkinson disease, and suggested that the formation of intracellular inclusions may be beneficial to cells and that a mutation in synphilin-1 that reduces this ability may sensitize neurons to cellular stress. The first patient presented at 66 years of age with a 3-year history of progressive slowing of movement and painful legs. The second patient recognized difficulties in movements of his left arm at 69 years of age.
Myhre et al. (2008) identified the R621C variant in 4 of 300 Norwegian patients with Parkinson disease and in 10 of 412 controls, suggesting that it is a polymorphism and not associated with susceptibility to PD. Other variants in the synphilin-1 gene were also identified in both patients and controls. Myhre et al. (2008) concluded that changes in the SNCAIP gene are not associated with susceptibility to PD.
Chung, K. K. K., Zhang, Y., Lim, K. L., Tanaka, Y., Huang, H., Gao, J., Ross, C. A., Dawson, V. L., Dawson, T. M. Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nature Med. 7: 1144-1150, 2001. [PubMed: 11590439] [Full Text: https://doi.org/10.1038/nm1001-1144]
Engelender, S., Kaminsky, Z., Guo, X., Sharp, A. H., Amaravi, R. K., Kleiderlein, J. J., Margolis, R. L., Troncoso, J. C., Lanahan, A. A., Worley, P. F., Dawson, V. L., Dawson, T. M., Ross, C. A. Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions. Nature Genet. 22: 110-114, 1999. [PubMed: 10319874] [Full Text: https://doi.org/10.1038/8820]
Engelender, S., Wanner, T., Kleiderlein, J. J., Wakabayashi, K., Tsuji, S., Takahashi, H., Ashworth, R., Margolis, R. L., Ross, C. A. Organization of the human synphilin-1 gene, a candidate for Parkinson's disease. Mammalian Genome 11: 763-766, 2000. [PubMed: 10967135] [Full Text: https://doi.org/10.1007/s003350010123]
Eyal, A., Szargel, R., Avraham, E., Liani, E., Haskin, J., Rott, R., Engelender, S. Synphilin-1A: an aggregation-prone isoform of synphilin-1 that causes neuronal death and is present in aggregates from alpha-synucleinopathy patients. Proc. Nat. Acad. Sci. 103: 5917-5922, 2006. [PubMed: 16595633] [Full Text: https://doi.org/10.1073/pnas.0509707103]
Marx, F. P., Holzmann, C., Strauss, K. M., Li, L., Eberhardt, O., Gerhardt, E., Cookson, M. R., Hernandez, D., Farrer, M. J., Kachergus, J., Engelender, S., Ross, C. A., Berger, K., Schols, L., Schulz, J. B., Riess, O., Kruger, R. Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease. Hum. Molec. Genet. 12: 1223-1231, 2003. [PubMed: 12761037] [Full Text: https://doi.org/10.1093/hmg/ddg134]
Myhre, R., Klungland, H., Farrer, M. J., Aasly, J. O. Genetic association study of synphilin-1 in idiopathic Parkinson's disease. BMC Med. Genet. 9: 19, 2008. Note: Electronic Article. [PubMed: 18366718] [Full Text: https://doi.org/10.1186/1471-2350-9-19]
Nuber, S., Franck, T., Wolburg, H., Schumann, U., Casadei, N., Fischer, K., Calaminus, C., Pichler, B. J., Chanarat, S., Teismann, P., Schulz, J. B., Luft, A. R., Tomiuk, J., Wilbertz, J., Bornemann, A., Kruger, R., Riess, O. Transgenic overexpression of the alpha-synuclein interacting protein synphilin-1 leads to behavioral and neuropathological alterations in mice. Neurogenetics 11: 107-120, 2010. [PubMed: 19760259] [Full Text: https://doi.org/10.1007/s10048-009-0212-2]
Smith, W. W., Liu, Z., Liang, Y., Masuda, N., Swing, D. A., Jenkins, N. A., Copeland, N. G., Troncoso, J. C., Pletnikov, M., Dawson, T. M., Martin, L. J., Moran, T. H., Lee, M. K., Borchelt, D. R., Ross, C. A. Synphilin-1 attenuates neuronal degeneration in the A53T alpha-synuclein transgenic mouse model. Hum. Molec. Genet. 19: 2087-2098, 2010. [PubMed: 20185556] [Full Text: https://doi.org/10.1093/hmg/ddq086]
Tsai, Y.-C., Riess, O., Soehn, A. S.,, Nguyen, H. P. The guanine nucleotide exchange factor kalirin-7 is a novel synphilin-1 interacting protein and modifies synphilin-1 aggregate transport and formation. PLoS One 7: e51999, 2012. Note: Electronic Article. [PubMed: 23284848] [Full Text: https://doi.org/10.1371/journal.pone.0051999]