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FLASH GENE

Symbol

SNCA

contributors: mct - updated : 20-08-2017

HGNC name	synuclein, alpha (non A4 component of amyloid precursor)
HGNC id	11138

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	PARK1 Parkinson disease, 1
Location	4q22.1      Physical location : 90.645.250 - 90.759.447
Synonym name	non A-beta component of AD amyloid
	alpha-synuclein
Synonym symbol(s)	NACP, PD1, PARK1, PARK4, NACP112, NACP140, aSYN

DNA

TYPE	functioning gene
STRUCTURE	111.43 kb     6 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site   enhancer
motif	repetitive sequence
text structure	three sp1 binding sites, polymorphic NACP-Rep1 elements modulating the activity of SNCA promoter/enhancer

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000345 6 - 3215 NP_000336 14.46 140 - 2014 2462967 containing exons 2a & 6a (longer than 2b & 6b respectively) encoding for the longest isoform also called NACP140 NM_001146054 4 splicing 3211 NP_001139526 14.46 140 fetal and adult brain (highly) and skeletal muscle, pancreas, not in liver 2014 2462967 containing exons 2b et 6b (shorter than 2a et 6a respectively) lacking exons 1 & 5 also called NACP112 NM_001146055 5 splicing 3022 NP_001139527 14.46 140 ubiquination by Parkin in the brain 2014 2462967 lacking exon 3 encoding for a soluble ant glycosylated isoform also called ASP22 NM_007308 4 - 3127 NP_009292 - 112 - 2014 2462967 SNCA112

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Digestive intestine small intestine     highly Endocrine pancreas       moderately Nervous brain       highly   nerve       highly Skin/Tegument skin       moderately Urinary bladder       moderately

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial secretory glandular endocrine   Muscular striatum skeletal     Nervous peripherous

cells

System Cell Pubmed Species Stage Rna symbol Nervous neuron

cell lineage
cell lines	highly in ovarian and breast carcinomas
fluid/secretion

at STAGE

physiological period

fetal

Text

brain

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	seven imperfect repeats of 11 aminoacids with the consensus core KTKEGV, homolog to 14-3-3 proteins YWHAs
	a twelve amino-acids stretch in the hydrophobic domain essential for filament assembly
	C-terminal peptide with a second acidic repat important for the chaperone activity

conjugated

ubiquitinated

HOMOLOGY

interspecies	homolog to rattus Snca (95.00 pc)
	homolog to murine Snca (95.00 pc)

Homologene

FAMILY

synuclein family

CATEGORY

chaperone/stress

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,mitochondria
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,Golgi
	intracellular,cytoplasm,organelle,lysosome
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus
text	concentrated in presynaptic nerve terminals
	mitochondrial translocation is promoted by intracellular acidification

basic FUNCTION	involved in exocytosis of synaptic vesicles, in synapse maintenance and plasticity
	induction of mitochondrial dysfunction and oxidative stress
	contributing to cell death in neurodegenerative diseases and accumulating in dentritic neurites and in Lewy bodies (neuronal and oligoendrocytic aggregates)
	regulating vesicles recycling via its inhibition of PLD2 and/or its ability to bind fatty acids
	playing a vital role in the modulation of dopamine transporter (DAT) function
	negative regulator of synaptic vesicle priming before fusion, that causes general defects in vesicle trafficking, to which dopaminergic neurons are especially sensitive
	direct role in mitochondrial physiology, especially under pathological conditions, and in principle, link SNCA to other Parkinson disease genes in regulating mitochondrial homeostasis
	likely SNCA protein levels hardly affect mitochondrial morphology in normal cell lines, but may have some influence on that under certain environmental conditions
	may modulate neurite outgrowth by interacting with the cytoskeletal protein SPTBN1
	soluble SNCA is a novel modulator of Alzheimer disease pathophysiology
	role of SNCA in adult hippocampal neurogenesis
	is normally secreted from neuronal cells and can thus exert paracrine effects
	is potentially able to reduce iron using copper as its catalytic centre
	tight link between the intracellular level of SNCA and maturation capacity of primary oligodendrocyte progenitor cells
	because both SNCA and CPLX1 modulate vesicle release, likely presynaptic dysfunction is an early event in Parkinson disease pathology
	promotes SNARE complex assembly at the presynaptic plasma membrane in its multimeric membrane-bound state, but not in its monomeric cytosolic state
	is transported into and out of the brain by the blood-brain barrier
	is shown to cause mitochondrial impairment through interaction with permeability transition pore complex
	extracellular SNCA alters synaptic transmission in brain neurons by perforating the neuronal plasma membrane
	TPPP and SNCA have two key features: they are disordered and co-enriched/co-localized in brain inclusions

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

non A/beta constituent of Alzheimer amyloid precursor alpha

INTERACTION

DNA

RNA

small molecule
	role for iron in the translational control of SNCA expression, suggesting that iron chelation may be a valid approach to control SNCA levels in the brain

protein	synphilin 1 (SNCAIP) binding
	associating with PRKC and other proteins
	binding to 14-3-3 (YWAHs) and acting as a potential chaperone with UBCH7 (isoform ASP22)
	disrupts cellular Rab homeostasis
	the specific interaction between SNCA and SNCAIP provides mechanistic insights into the inclusion-body formation in cells and pathological implication in Parkinson disease
	binds TRAF6 that enhances its ubiquitination with atypical chains (possibility that SNCA might be an additional Parkinson disease-associated target of TRAF6 ligase activity)
	SNCA modulates vesicle trafficking through its interaction with RABAC1
	protects the integrity of PLCB1 and its ability to be activated by Galpha(q), which may in turn impact Ca2+ signaling
	likely modulates neurite outgrowth by interacting with cytoskeletal proteins such as SPTBN1
	is a substrate of PLK2, and elevated levels of SNCA prevent PLK2 from maintaining a normal level of GTP-bound RHO1, which is an essential GTPase that regulates stress signaling
	TOMM40 mediates mitochondrial dysfunction induced by SNCA accumulation in Parkinson disease
	TPPP lowered the mobility of autophagosomes and hindered the final maturation of autophagosomes by preventing their fusion with lysosomes for the final degradation of SNCA
	its overexpression may promote SRC activation and PPP2R4 inactivation, leading to hyperphosphorylation of proteins, and may lead to neurodegeneration in PD in part by suppressing the endogenous neuroprotective activity of PPP2R4
	SNCA interacts with GBA and efficiently inhibits enzyme activity
	PSAP a protein vital for GBA activity, protects GBA against SNCA inhibition
	ZSCAN21 expression decreases SNCA aggregation in the cells
	ENDOG is a critical downstream executor of SNCA cytotoxicity
	critical regulatory role for that endogenous CTSD activity in dopaminergic cells in SNCA homeostasis which cannot be compensated for by increased CTSB
	FOXO3 is an important determinant of neuronal survival in the substantia nigra, which may oppose SNCA accumulation and proteotoxicity
	PARK2 ubiquitination affects its protein stability and E3 ligase activity, possibly leading to SNCA sequestration and subsequent clearance
	interactions between VPS35, EIF4G1, and SNCA
	upon interacting with SNCA, HSPA5 activates a signaling cascade leading to cofilin 1 inactivation and stabilization of microfilaments
	ZSCAN21 plays an important regulatory role in SNCA transcription
	endolysosomal protein ATP13A2 can determine the fate of alpha-synuclein (SNCA)
	TRIM32 binds to the promoter region of SNCA, suggesting a novel mechanism of its transcriptional regulation
	regulatory role of DYRK1A in controlling MAPT and SNCA
	DNAJB6 and HSPA4 cooperate to suppress SNCA aggregation
	RER1 is a novel and potential important mediator of elevated SNCA levels
	TRIM17 and TRIM41 modulate SNCA expression by regulating ZSCAN21
	DDX10 is an enhancer of SNCA toxicity and oligomerization

cell & other

REGULATION

Phosphorylated by

PTPN1 (phosphorylation of SNCA is crucial in compensating for proteasomal dysfunction)

Other	regulated by PARP1(binding to NACP-Rep1)
	phosphorylated by PLK2 in neurons (Inglis, 2009)
	its monoubiquitylation by SIAH is decreased by SNCAIP
	NEDD4 overexpression enhances SNCA ubiquitination and clearance by a lysosomal process requiring components of the endosomal-sorting complex required for transport

ASSOCIATED DISORDERS

corresponding disease(s)

PARK1

related resource

Alpha - Synuclein Locus Mutation Database

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional   amplification     triplicated locus in Parkinson 4 (PARK4)

Susceptibility

to sporadic Parkinson disease (PD) to variability of age at onset of Parkinson's disease

Variant & Polymorphism SNP	"protective" genotype 259/259 of the PD-associated promoter repeat NACP-Rep1 is associated with lower protein levels in blood
	rs356219 risk allele in the SNCA gene significantly contributing to earlier age at onset

Candidate gene
Marker	increased SNCA and altered phagocytosis may provide a useful biomarker for human Parkinson disease
Therapy target
	System Type Disorder Pubmed neurology neurodegenerative Parkinson/dementia Parkinsonism secreted SNCA exerts toxicity through engagement, at least in part, of the Ca2+ homeostatic machinery, and therefore, manipulating Ca2+ signaling pathways might represent a potential therapeutic strategy for Parkinson disease

ANIMAL & CELL MODELS