Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH8VNOK)

• DOT Name: Synphilin-1 (SNCAIP)
• Synonyms: Sph1; Alpha-synuclein-interacting protein
• Gene Name: SNCAIP
• Related Disease:
  Lewy body dementia
  Alzheimer disease
  Neuroblastoma
  Parkinson disease
  Progressive supranuclear palsy
  Dementia
  Diphtheria
  Ovarian neoplasm
• UniProt ID: SNCAP_HUMAN
• PDB ID: 2KES
• Pfam ID: PF12796 ; PF16700
• Sequence:
  MEAPEYLDLDEIDFSDDISYSVTSLKTIPELCRRCDTQNEDRSVSSSSWNCGISTLITNT
  QKPTGIADVYSKFRPVKRVSPLKHQPETLENNESDDQKNQKVVEYQKGGESDLGPQPQEL
  GPGDGVGGPPGKSSEPSTSLGELEHYDLDMDEILDVPYIKSSQQLASFTKVTSEKRILGL
  CTTINGLSGKACSTGSSESSSSNMAPFCVLSPVKSPHLRKASAVIHDQHKLSTEETEISP
  PLVKCGSAYEPENQSKDFLNKTFSDPHGRKVEKTTPDCQLRAFHLQSSAAESKPEEQVSG
  LNRTSSQGPEERSEYLKKVKSILNIVKEGQISLLPHLAADNLDKIHDENGNNLLHIAASQ
  GHAECLQHLTSLMGEDCLNERNTEKLTPAGLAIKNGQLECVRWMVSETEAIAELSCSKDF
  PSLIHYAGCYGQEKILLWLLQFMQEQGISLDEVDQDGNSAVHVASQHGYLGCIQTLVEYG
  ANVTMQNHAGEKPSQSAERQGHTLCSRYLVVVETCMSLASQVVKLTKQLKEQTVERVTLQ
  NQLQQFLEAQKSEGKSLPSSPSSPSSPASRKSQWKSPDADDDSVAKSKPGVQEGIQVLGS
  LSASSRARPKAKDEDSDKILRQLLGKEISENVCTQEKLSLEFQDAQASSRNSKKIPLEKR
  ELKLARLRQLMQRSLSESDTDSNNSEDPKTTPVRKADRPRPQPIVESVESMDSAESLHLM
  IKKHTLASGGRRFPFSIKASKSLDGHSPSPTSESSEPDLESQYPGSGSIPPNQPSGDPQQ
  PSPDSTAAQKVATSPKSALKSPSSKRRTSQNLKLRVTFEEPVVQMEQPSLELNGEKDKDK
  GRTLQRTSTSNESGDQLKRPFGAFRSIMETLSGNQNNNNNYQAANQLKTSTLPLTSLGRK
  TDAKGNPASSASKGKNKAA
• Function: Isoform 2 inhibits the ubiquitin ligase activity of SIAH1 and inhibits proteasomal degradation of target proteins. Isoform 2 inhibits autoubiquitination and proteasomal degradation of SIAH1, and thereby increases cellular levels of SIAH. Isoform 2 modulates SNCA monoubiquitination by SIAH1.
• Tissue Specificity: Detected in brain (at protein level). Widely expressed, with highest levels in brain, heart and placenta.
• KEGG Pathway:
  Parkinson disease (hsa05012)
  Pathways of neurodegeneration - multiple diseases (hsa05022)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lewy body dementia	DISAE66J	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[2]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[3]
Parkinson disease	DISQVHKL	Strong	Biomarker	[3]
Progressive supranuclear palsy	DISO5KRQ	Strong	Genetic Variation	[4]
Dementia	DISXL1WY	Limited	Genetic Variation	[5]
Diphtheria	DISZWM55	Limited	Biomarker	[6]
Ovarian neoplasm	DISEAFTY	Limited	Genetic Variation	[7]

6 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Synphilin-1 (SNCAIP).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Synphilin-1 (SNCAIP).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Synphilin-1 (SNCAIP).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Synphilin-1 (SNCAIP).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Synphilin-1 (SNCAIP).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Synphilin-1 (SNCAIP).	[8]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Synphilin-1 (SNCAIP).	[9]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Synphilin-1 (SNCAIP).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Synphilin-1 (SNCAIP).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Synphilin-1 (SNCAIP).	[12]

References

• [1] Synphilin-1-binding protein NUB1 is colocalized with nonfibrillar, proteinase K-resistant -synuclein in presynapses in Lewy body disease.J Neuropathol Exp Neurol. 2011 Oct;70(10):879-89. doi: 10.1097/NEN.0b013e3182303745.
• [2] Parkin and synphilin-1 isoform expression changes in Lewy body diseases.Neurobiol Dis. 2007 Jun;26(3):681-7. doi: 10.1016/j.nbd.2007.03.007. Epub 2007 Mar 27.
• [3] Synphilin-1 has neuroprotective effects on MPP(+)-induced Parkinson's disease model cells by inhibiting ROS production and apoptosis.Neurosci Lett. 2019 Jan 18;690:145-150. doi: 10.1016/j.neulet.2018.10.020. Epub 2018 Oct 11.
• [4] Multiple system atrophy/progressive supranuclear palsy: alpha-Synuclein, synphilin, tau, and APOE.Neurology. 2000 Dec 26;55(12):1918-20. doi: 10.1212/wnl.55.12.1918.
• [5] Differential expression of alpha-synuclein, parkin, and synphilin-1 isoforms in Lewy body disease.Neurogenetics. 2008 Jul;9(3):163-72. doi: 10.1007/s10048-008-0124-6. Epub 2008 Mar 12.
• [6] Genetic construction, expression, and melanoma-selective cytotoxicity of a diphtheria toxin-related alpha-melanocyte-stimulating hormone fusion protein.Proc Natl Acad Sci U S A. 1986 Nov;83(21):8258-62. doi: 10.1073/pnas.83.21.8258.
• [7] Genome-Wide Study of Response to Platinum, Taxane, and Combination Therapy in Ovarian Cancer: In vitro Phenotypes, Inherited Variation, and Disease Recurrence.Front Genet. 2016 Mar 22;7:37. doi: 10.3389/fgene.2016.00037. eCollection 2016.
• [8] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [9] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [10] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [11] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [14] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [15] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.