Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT08OSU)

• DTT Name: Synuclein alpha (SNCA)
• Synonyms: PARK1; Non-A4 component of amyloid precursor; Non-A beta component of AD amyloid; NACP; Alpha-synuclein
• Gene Name: SNCA
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Synuclein
• UniProt ID: SYUA_HUMAN
• TTD ID: T03644
• 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. Plays also a role in the regulation of the dopamine neurotransmission by associating with the dopamine transporter (DAT1) and thereby modulating its activity.
• KEGG Pathway:
  Alzheimer's disease (hsa05010)
  Parkinson's disease (hsa05012)
• Reactome Pathway: Amyloid formation (R-HSA-977225)

Molecular Interaction Atlas (MIA) of This DTT

10 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BIIB054	DMZO2SY	Parkinson disease	8A00.0	Phase 2	[2]
PRX002	DMKTP8E	Parkinson disease	8A00.0	Phase 2	[3]
RG7935	DME1YMX	Parkinson disease	8A00.0	Phase 2	[1]
TAK-341	DM6D30Q	Multiple system atrophy	8D87.0	Phase 2	[4]
Anle138b	DMEC8E2	Parkinson disease	8A00.0	Phase 1	[5]
MEDI1341	DMQDBSU	Parkinson disease	8A00.0	Phase 1	[2]
NPT200-11	DMFDBV5	Multiple system atrophy	8D87.0	Phase 1	[6]
Posiphen R-phenserine	DMCU54M	Alzheimer disease	8A20	Phase 1	[7]
SAR446159	DMWAO33	Parkinson disease	8A00.0	Phase 1	[8]
UCB7853	DMD7I23	Parkinson disease	8A00.0	Phase 1	[9]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Parkinson's disease	8A00.0	Substantia nigra tissue	1.04E-01	-0.26	-0.33
Alzheimer's disease	8A00.0	Entorhinal cortex	7.86E-08	-0.64	-0.92

References

• [1] alpha-Synuclein in Parkinson's Disease. Cold Spring Harb Perspect Med. 2012 February; 2(2): a009399.
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti-alpha-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease: A Randomized Clinical Trial. JAMA Neurol. 2018 Oct 1;75(10):1206-1214.
• [4] Preclinical development of a high affinity alpha-synuclein antibody, MEDI1341, that can enter the brain, sequester extracellular alpha-synuclein and attenuate alpha-synuclein spreading in vivo. Neurobiol Dis. 2019 Dec;132:104582.
• [5] Anle138b interaction in alpha-synuclein aggregates by dynamic nuclear polarization NMR. Methods. 2023 Jun;214:18-27.
• [6] The small molecule alpha-synuclein misfolding inhibitor, NPT200-11, produces multiple benefits in an animal model of Parkinson's disease. Sci Rep. 2018 Nov 1;8(1):16165.
• [7] The Anticholinesterase Phenserine and Its Enantiomer Posiphen as 5 ntranslated-Region-Directed Translation Blockers of the Parkinson's Alpha Synuclein Expression. Parkinson's Disease Volume 2012 (2012), Article ID 142372, Page(13).
• [8] Clinical pipeline report, company report or official report of Sanofi
• [9] ClinicalTrials.gov (NCT04651153) A Multicenter, Participant-Blind, Investigator-Blind, Randomized, Placebo-Controlled Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses of UCB7853 in Healthy Male Study Participants and Multiple Ascending Doses in Patients With Parkinson's Disease. U.S.National Institutes of Health.