Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPWC1MR)

• DOT Name: Alpha-synuclein (SNCA)
• Synonyms: Non-A beta component of AD amyloid; Non-A4 component of amyloid precursor; NACP
• Gene Name: SNCA
• Related Disease:
  Autosomal dominant Parkinson disease 4
  Parkinson disease
  Autosomal dominant Parkinson disease 1
  Lewy body dementia
  Obsolete hereditary late onset Parkinson disease
  Parkinsonian-pyramidal syndrome
• UniProt ID: SYUA_HUMAN
• PDB ID: 1XQ8 ; 2JN5 ; 2KKW ; 2M55 ; 2N0A ; 2X6M ; 3Q25 ; 3Q26 ; 3Q27 ; 3Q28 ; 3Q29 ; 4BXL ; 4R0U ; 4R0W ; 4RIK ; 4RIL ; 4ZNN ; 5CRW ; 6A6B ; 6CT7 ; 6CU7 ; 6CU8 ; 6H6B ; 6I42 ; 6L1T ; 6L1U ; 6L4S ; 6LRQ ; 6OSJ ; 6OSL ; 6OSM ; 6PEO ; 6PES ; 6RT0 ; 6RTB ; 6SST ; 6SSX ; 6UFR ; 6XYO ; 6XYP ; 6XYQ ; 7C1D ; 7E0F ; 7L7H ; 7LC9 ; 7NCA ; 7NCG ; 7NCH ; 7NCI ; 7NCJ ; 7NCK ; 7OZG ; 7OZH ; 7STX ; 7UAK ; 7V47 ; 7V48 ; 7V49 ; 7V4A ; 7V4B ; 7V4C ; 7V4D ; 7WMM ; 7WNZ ; 7WO0 ; 7XJX ; 7XO0 ; 7XO1 ; 7XO2 ; 7XO3 ; 7YK2 ; 7YK8 ; 7YNF ; 7YNG ; 7YNL ; 7YNM ; 7YNN ; 7YNO ; 7YNP ; 7YNQ ; 7YNR ; 7YNS ; 7YNT ; 8A4L ; 8A9L ; 8ADS ; 8ADU ; 8ADV ; 8ADW ; 8AEX ; 8BQV ; 8BQW ; 8CE7 ; 8CEB ; 8CYR ; 8CYS ; 8CYT ; 8CYV ; 8CYW ; 8CYX ; 8CYY ; 8CZ0 ; 8CZ1 ; 8CZ2 ; 8CZ3 ; 8CZ6 ; 8FPT ; 8G0L ; 8GF7 ; 8H03 ; 8H04 ; 8H05
• Pfam ID: PF01387
• Sequence:
  MDVFMKGLSKAKEGVVAAAEKTKQGVAEAAGKTKEGVLYVGSKTKEGVVHGVATVAEKTK
  EQVTNVGGAVVTGVTAVAQKTVEGAGSIAAATGFVKKDQLGKNEEGAPQEGILEDMPVDP
  DNEAYEMPSEEGYQDYEPEA
• Function: Neuronal protein that plays several roles in synaptic activity such as regulation of synaptic vesicle trafficking and subsequent neurotransmitter release. Participates as a monomer in synaptic vesicle exocytosis by enhancing vesicle priming, fusion and dilation of exocytotic fusion pores. Mechanistically, acts by increasing local Ca(2+) release from microdomains which is essential for the enhancement of ATP-induced exocytosis. Acts also as a molecular chaperone in its multimeric membrane-bound state, assisting in the folding of synaptic fusion components called SNAREs (Soluble NSF Attachment Protein REceptors) at presynaptic plasma membrane in conjunction with cysteine string protein-alpha/DNAJC5. This chaperone activity is important to sustain normal SNARE-complex assembly during aging. Also plays a role in the regulation of the dopamine neurotransmission by associating with the dopamine transporter (DAT1) and thereby modulating its activity.
• Tissue Specificity: Highly expressed in presynaptic terminals in the central nervous system. Expressed principally in brain.
• KEGG Pathway:
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway:
  PKR-mediated signaling (R-HSA-9833482)
  Amyloid fiber formation (R-HSA-977225)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant Parkinson disease 4	DIS1WEB8	Definitive	Autosomal dominant	[1]
Parkinson disease	DISQVHKL	Definitive	Autosomal dominant	[2]
Autosomal dominant Parkinson disease 1	DISGSYXL	Strong	Autosomal dominant	[3]
Lewy body dementia	DISAE66J	Strong	Autosomal dominant	[3]
Obsolete hereditary late onset Parkinson disease	DISCT6PQ	Supportive	Autosomal dominant	[4]
Parkinsonian-pyramidal syndrome	DISHIIPA	Supportive	Autosomal recessive	[5]

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Alpha-synuclein (SNCA) increases the response to substance of Hydrogen peroxide.	[35]
Methamphetamine	DMPM4SK	Approved	Alpha-synuclein (SNCA) increases the response to substance of Methamphetamine.	[36]
Dopamine	DMPGUCF	Approved	Alpha-synuclein (SNCA) increases the response to substance of Dopamine.	[37]
Aluminium	DM6ECN9	Approved	Alpha-synuclein (SNCA) affects the response to substance of Aluminium.	[40]
Paraquat	DMR8O3X	Investigative	Alpha-synuclein (SNCA) increases the response to substance of Paraquat.	[35]

This DOT Affected the Regulation of Drug Effects of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Adenosine triphosphate	DM79F6G	Approved	Alpha-synuclein (SNCA) decreases the abundance of Adenosine triphosphate.	[38]
Glutathione	DMAHMT9	Approved	Alpha-synuclein (SNCA) decreases the abundance of Glutathione.	[39]
Oxidized glutathione	DM9EQC0	Approved	Alpha-synuclein (SNCA) decreases the abundance of Oxidized glutathione.	[41]

26 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 Alpha-synuclein (SNCA).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Alpha-synuclein (SNCA).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Alpha-synuclein (SNCA).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Alpha-synuclein (SNCA).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Alpha-synuclein (SNCA).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Alpha-synuclein (SNCA).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Alpha-synuclein (SNCA).	[13]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Alpha-synuclein (SNCA).	[14]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Alpha-synuclein (SNCA).	[15]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Alpha-synuclein (SNCA).	[16]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Alpha-synuclein (SNCA).	[17]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Alpha-synuclein (SNCA).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Alpha-synuclein (SNCA).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Alpha-synuclein (SNCA).	[21]
AMEP	DMFELMQ	Phase 1	AMEP increases the expression of Alpha-synuclein (SNCA).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Alpha-synuclein (SNCA).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Alpha-synuclein (SNCA).	[26]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Alpha-synuclein (SNCA).	[27]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Alpha-synuclein (SNCA).	[28]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Alpha-synuclein (SNCA).	[22]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Alpha-synuclein (SNCA).	[29]
27-hydroxycholesterol	DM2L6OZ	Investigative	27-hydroxycholesterol increases the expression of Alpha-synuclein (SNCA).	[32]
GW-3965	DMG60ET	Investigative	GW-3965 increases the expression of Alpha-synuclein (SNCA).	[32]
T0901317	DMZQVDI	Investigative	T0901317 increases the expression of Alpha-synuclein (SNCA).	[32]
Buthionine sulfoximine	DMJ46CB	Investigative	Buthionine sulfoximine increases the expression of Alpha-synuclein (SNCA).	[33]
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine	DMPWB8G	Investigative	1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine increases the expression of Alpha-synuclein (SNCA).	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Alpha-synuclein (SNCA).	[10]
MG-132	DMKA2YS	Preclinical	MG-132 increases the phosphorylation of Alpha-synuclein (SNCA).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Alpha-synuclein (SNCA).	[24]
Octanal	DMTN0OK	Investigative	Octanal increases the methylation of Alpha-synuclein (SNCA).	[31]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the degradation of Alpha-synuclein (SNCA).	[20]

1 Drug(s) Affected the Biochemical Pathways of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
acrolein	DMAMCSR	Investigative	acrolein affects the metabolism of Alpha-synuclein (SNCA).	[30]

References

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