Affinage

SNCA

Alpha-synuclein · UniProt P37840

Round 2 corrected
Length
140 aa
Mass
14.5 kDa
Annotated
2026-04-28
130 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

α-Synuclein (SNCA) is a presynaptic, natively unfolded protein that functions as a non-classical chaperone promoting SNARE-complex assembly through direct binding to synaptobrevin-2/VAMP2, and whose misfolding and aggregation into phospho-Ser129-positive amyloid filaments underlies Parkinson's disease and related synucleinopathies (PMID:20798282, PMID:11813001). Pathogenic point mutations (A53T, A30P, E46K, A30G), gene duplications, or triplications cause dose-dependent dopaminergic neurodegeneration by promoting fibril formation, blocking ER-to-Golgi trafficking, activating microglial NADPH oxidase, and propagating between neurons via endocytosis (PMID:9197268, PMID:16794039, PMID:15791003, PMID:19651612, PMID:14593171). α-Synuclein is normally cleared through chaperone-mediated autophagy and the autophagy–lysosome pathway, where cathepsin D serves as a critical lysosomal protease and a bidirectional feedback loop with glucocerebrosidase/glucosylceramide modulates its lysosomal turnover (PMID:15333840, PMID:35287553, PMID:21700325). Dopamine oxidatively ligates to α-synuclein and stabilizes toxic protofibrillar intermediates, providing a molecular basis for the selective vulnerability of dopaminergic neurons, while molecular chaperones such as Hsp70 suppress α-synuclein-mediated neurodegeneration (PMID:11701929, PMID:11823645).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1993 High

    Identification of SNCA as the precursor of NAC, a component of AD amyloid, established its amyloidogenic potential and provided the molecular clone needed for all subsequent functional studies.

    Evidence cDNA cloning, amino acid sequencing, immunoblot, and secondary structure prediction from human brain

    PMID:8248242

    Open questions at the time
    • Physiological function completely unknown
    • Relationship to neurodegeneration beyond AD amyloid association unclear
  2. 1996 High

    Biophysical characterization revealed α-synuclein is natively unfolded, lacking stable secondary structure or a hydrophobic core, which explained its unusual biochemical behavior and raised questions about how a disordered protein could form ordered aggregates.

    Evidence Analytical ultracentrifugation, CD, FTIR, gel filtration on recombinant protein

    PMID:8901511

    Open questions at the time
    • Whether unfolded state is the sole physiological conformation (later challenged by tetramer hypothesis)
    • Mechanism by which an unfolded protein nucleates amyloid not addressed
  3. 1997 High

    The A53T mutation co-segregating with autosomal dominant PD in multiple families, combined with α-synuclein immunoreactivity in all Lewy bodies, established SNCA as the first PD gene and its protein as the principal Lewy body component.

    Evidence Linkage analysis and sequencing in Italian/Greek PD families; double-label immunohistochemistry on sporadic PD brain

    PMID:9197268 PMID:9547168

    Open questions at the time
    • Mechanism by which A53T causes disease not yet known
    • Whether wild-type α-synuclein contributes to sporadic PD unresolved
  4. 1998 High

    Discovery of A30P as a second causative SNCA mutation confirmed that the gene is a bona fide PD locus and that multiple positions in α-synuclein's N-terminal repeat region are vulnerable to pathogenic substitution.

    Evidence Mutation screening and co-segregation in a German PD family

    PMID:9462735

    Open questions at the time
    • Structural basis for how A30P differs mechanistically from A53T unknown
  5. 2001 High

    Two discoveries resolved key aspects of α-synuclein toxicity: dopamine oxidative ligation stabilizes toxic protofibrillar intermediates (explaining dopaminergic selectivity), and Hsp70 chaperone activity suppresses α-synuclein-induced dopaminergic neuron loss (identifying the protein quality control axis as protective).

    Evidence In vitro fibril formation with dopamine-adduct characterization; transgenic Drosophila with Hsp70 co-expression and genetic epistasis

    PMID:11701929 PMID:11823645

    Open questions at the time
    • Whether dopamine-stabilized protofibrils are the toxic species in vivo unproven
    • Hsp70 mechanism of action on α-synuclein (refolding vs disaggregation vs degradation) not defined
  6. 2002 High

    Identification of Ser129 phosphorylation as the dominant pathological modification and visualization of annular protofibrillar structures for mutant α-synuclein established a post-translational and structural framework for synucleinopathy.

    Evidence Mass spectrometry and phospho-specific antibodies on disease brain; electron microscopy of recombinant mutant assemblies

    PMID:11813001 PMID:12124613

    Open questions at the time
    • Whether Ser129 phosphorylation is causally required for aggregation or merely correlative in vivo
    • Identity of the kinase(s) responsible in vivo not resolved
  7. 2003 High

    SNCA locus triplication causing early-onset PD with dementia proved that increased dosage of wild-type α-synuclein alone suffices for disease, fundamentally reframing PD pathogenesis as a gene-dose problem.

    Evidence Genomic dosage analysis and FISH in a large Iowa kindred

    PMID:14593171

    Open questions at the time
    • Threshold of expression increase needed for pathogenesis not defined
    • Mechanism linking overexpression to selective dopaminergic vulnerability unclear
  8. 2004 High

    Identification of E46K as a third causative mutation and SNCA duplication as a milder dose-dependent PD cause, together with discovery that wild-type α-synuclein is cleared via CMA while mutants block the pathway, connected genetic dose and mutant-specific toxicity to the lysosomal degradation axis.

    Evidence E46K family co-segregation with neuropathology; FISH for duplication; in vitro CMA reconstitution with lysosomal uptake and receptor-binding assays

    PMID:14755719 PMID:15333840 PMID:15451224

    Open questions at the time
    • Whether CMA blockade by mutant α-synuclein is sufficient for disease in vivo
    • Relative contribution of CMA versus macroautophagy to α-synuclein clearance in neurons not quantified
  9. 2006 High

    A yeast genome-wide screen identified Rab1-sensitive ER-to-Golgi trafficking as the primary pathway blocked by α-synuclein accumulation, validated across C. elegans and rat neurons, establishing vesicular trafficking disruption as a core cytotoxic mechanism.

    Evidence Genome-wide overexpression/deletion screen in yeast; ER-to-Golgi assay; cross-species rescue experiments

    PMID:16794039

    Open questions at the time
    • Whether ER-to-Golgi block is a direct stoichiometric effect of α-synuclein on vesicle fusion or indirect
    • Mammalian Rab GTPases other than Rab1 that may compensate not explored
  10. 2009 High

    Demonstration that α-synuclein transmits from affected to naïve neurons via endocytosis and seeds Lewy-like inclusions in recipient cells established prion-like propagation as a disease mechanism.

    Evidence Co-culture transmission assay with endocytosis inhibition; grafting into transgenic mouse brain; caspase 3 activation in recipient cells

    PMID:19651612

    Open questions at the time
    • Receptor or uptake mechanism for α-synuclein entry into recipient cells not identified
    • Whether propagation drives disease progression in human PD unproven
  11. 2010 High

    Reconstitution of α-synuclein's physiological function showed it directly binds VAMP2 and promotes SNARE-complex assembly, with triple-synuclein knockout mice developing age-dependent neurological impairment, establishing α-synuclein as a presynaptic SNARE chaperone.

    Evidence Recombinant protein binding and SNARE assembly reconstitution; triple-knockout mouse phenotyping with brain biochemistry

    PMID:20798282

    Open questions at the time
    • Redundancy among synuclein family members for SNARE chaperoning not fully dissected
    • Whether loss of SNARE chaperone function contributes to PD pathogenesis distinct from gain-of-toxic-function
  12. 2011 High

    Two parallel advances reshaped the field: endogenous α-synuclein exists as a helically folded tetramer resistant to aggregation (challenging the unfolded monomer paradigm), and GCase loss creates a bidirectional pathogenic loop where glucosylceramide stabilizes α-synuclein oligomers while α-synuclein inhibits GCase activity.

    Evidence Analytical ultracentrifugation and EM on endogenous protein; iPSC-derived neurons and in vitro GlcCer–α-synuclein aggregation assay with GCase activity in PD brain

    PMID:21700325 PMID:21841800

    Open questions at the time
    • Tetramer versus monomer debate not fully resolved—conditions of native isolation remain debated
    • Quantitative contribution of GCase–α-synuclein loop to sporadic PD unknown
  13. 2015 High

    Injection of structurally defined α-synuclein strains (oligomers, ribbons, fibrils) into rat brain produced distinct pathological and behavioral phenotypes, establishing the prion strain concept for synucleinopathies and demonstrating that fibrils cross the blood-brain barrier.

    Evidence Intracerebral and intravenous injection of characterized assemblies; behavioral testing and neuropathology

    PMID:26061766

    Open questions at the time
    • Whether strain-specific folds found in animal models correspond to human disease subtypes not confirmed
    • Mechanism of blood-brain barrier crossing unknown
  14. 2018 High

    Epigenome editing at SNCA intron 1 using dCas9-DNMT3A rescued disease phenotypes in triplication patient-derived neurons, and CRISPR deletion of SNCA abolished PFF-seeded aggregation, together establishing intron 1 methylation as a transcriptional regulator and endogenous α-synuclein as required for seeded pathology.

    Evidence dCas9-DNMT3A lentiviral system in triplication iPSC-DA neurons; CRISPR/Cas9n SNCA knockout in hESC-derived mDA neurons with PFF seeding

    PMID:30266652 PMID:30472757

    Open questions at the time
    • Therapeutic window for methylation-based SNCA reduction not defined
    • Whether complete SNCA elimination has long-term detrimental effects on synaptic function
  15. 2022 High

    Recombinant cathepsin D replacement in iPSC-derived A53T neurons and ctsd-KO mice cleared pathological α-synuclein conformers and restored endo-lysosomal function, establishing CTSD as the critical lysosomal protease for α-synuclein degradation.

    Evidence Enzyme replacement therapy in patient iPSC-DA neurons and ctsd-KO mouse brain; SIM imaging, Western blot fractionation, lysosomal targeting assays

    PMID:35287553

    Open questions at the time
    • Whether CTSD is rate-limiting in sporadic PD lysosomes not established
    • Delivery of recombinant CTSD to human brain not demonstrated
  16. 2023 High

    Cryo-EM of brain-derived filaments from a patient with a 21-nucleotide SNCA insertion revealed a novel α-synuclein fold distinct from Lewy body and MSA folds, with a non-proteinaceous cofactor, strengthening the concept that distinct structural polymorphs underlie distinct synucleinopathies.

    Evidence Cryo-EM structure determination of sarkosyl-insoluble filaments from JOS patient brain; comparison with in vitro assembled filaments

    PMID:36847833

    Open questions at the time
    • Identity of the non-proteinaceous cofactor unknown
    • Whether the JOS fold can be reproduced in vitro with the correct cofactor not achieved
    • Structural basis for strain-specific toxicity not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the physiological α-synuclein conformation in vivo (tetramer vs. monomer equilibrium), the receptor mediating cell-to-cell propagation, the structural determinants of strain-specific toxicity, and whether loss of SNARE chaperone function contributes to disease independently of toxic aggregation.
  • Native quaternary state in living neurons remains debated
  • No receptor for α-synuclein uptake during propagation identified
  • Relative contribution of loss-of-function versus gain-of-toxic-function to PD not quantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 2 GO:0005198 structural molecule activity 1 GO:0044183 protein folding chaperone 1
Localization
GO:0005764 lysosome 3 GO:0005829 cytosol 2 GO:0031410 cytoplasmic vesicle 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-9612973 Autophagy 6 R-HSA-1643685 Disease 5 R-HSA-112316 Neuronal System 2 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-5357801 Programmed Cell Death 1
Partners
CPLX1CTSDGBAHSPA1ARAB1AVAMP2
Complex memberships
SNARE complex (as chaperone, not stable subunit)

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 SNCA (NACP) was molecularly cloned as the precursor of NAC (non-Aβ component of AD amyloid), a 140-amino-acid protein (Mr ~19 kDa) found in the cytosolic fraction of brain homogenates and identified as a second component of purified AD amyloid; its NAC peptide sequence has strong β-structure-forming tendency consistent with amyloid association. cDNA cloning, amino acid sequencing, immunoblot, immunohistochemistry, secondary structure prediction Proceedings of the National Academy of Sciences of the United States of America High 8248242
1996 Human NACP/α-synuclein is a natively unfolded protein: it has a Stokes radius (34 Å) and sedimentation coefficient (1.7S) inconsistent with a globular fold, lacks significant secondary structure by CD and FTIR, has no hydrophobic core, and exists as rapidly equilibrating extended conformers—properties unchanged by boiling, pH, salt, or denaturants. Analytical ultracentrifugation, circular dichroism (CD), FTIR, UV spectroscopy, gel filtration Biochemistry High 8901511
1996 NACP/α-synuclein is a presynaptic protein colocalized with synaptophysin-immunoreactive structures; in Alzheimer's disease brain its concentration per synaptic structure increases while overall synaptic number decreases, and NAC immunoreactivity is found in the amyloid core of neuritic/diffuse plaques, implicating SNCA in amyloid formation. Semiquantitative immunoblot, confocal immunofluorescence, computer-aided morphometry The American journal of pathology Medium 8546207
1995 The SNCA/NACP gene is the human homolog of rat synuclein, maps to chromosome 4, and is expressed as at least three alternatively spliced transcripts in lymphocytes; sequencing the entire coding region in 26 familial early-onset AD patients found no mutations. Homology search, chromosomal mapping, RT-PCR, direct sequencing Genomics Medium 7601450
1997 A missense mutation (A53T) in the SNCA gene co-segregates with autosomal dominant Parkinson's disease in an Italian kindred and three unrelated Greek families, identifying SNCA as the first gene causally linked to PD. Linkage analysis, mutation screening by sequencing, family-based genetic study Science (New York, N.Y.) High 9197268
1997 NACP/α-synuclein immunoreactivity is present in Lewy bodies and degenerating neurites in sporadic Parkinson's disease brain; all ubiquitin-immunoreactive Lewy bodies are also NACP-immunoreactive, establishing SNCA as a core component of Lewy bodies. Immunohistochemistry with anti-NACP and anti-ubiquitin antibodies on serial sections Neuroscience letters High 9547168
1997 NACP/α-synuclein expression is upregulated during phorbol ester-induced megakaryocytic differentiation in K562 cells while β-synuclein is downregulated; in platelets, NACP is loosely associated with the plasma membrane, endomembrane system, and membranes of secretory α-granules, demonstrating membrane association in a non-neuronal context. Immunoblot, immunogold electron microscopy, cell differentiation assay Biochemical and biophysical research communications Medium 9299413
1998 A30P mutation in SNCA is identified in a German family with Parkinson's disease, establishing a second causative point mutation in α-synuclein. Mutation screening/sequencing, family genetic study Nature genetics High 9462735
1998 NACP/α-synuclein shows transient upregulation and redistribution around cerebral blood vessels after 5-min ischemia in gerbil hippocampal CA1 subfield, with development of unusual tubal and chain-like NACP-positive structures at 6 months, implicating SNCA in ischemic pathogenesis. Immunohistochemistry at multiple time points after ischemia Brain research Low 9555070
2001 Expression of human α-synuclein in Drosophila causes dopaminergic neuron loss; directed expression of the molecular chaperone Hsp70 prevented this neuronal loss, and inhibition of endogenous chaperone activity accelerated α-synuclein toxicity—demonstrating that chaperone activity modulates SNCA-mediated neurodegeneration. Transgenic Drosophila, directed expression, dopaminergic neuron counting, genetic epistasis Science (New York, N.Y.) High 11823645
2001 Dopamine and related catecholamines inhibit α-synuclein fibril formation by oxidative ligation to the protein, selectively stabilizing the protofibril intermediate (preventing protofibril-to-fibril conversion), providing a mechanistic explanation for the dopaminergic selectivity of α-synuclein-associated neurotoxicity. In vitro fibril formation assay, compound library screen, biochemical characterization of dopamine–α-synuclein adducts Science (New York, N.Y.) High 11701929
2002 α-Synuclein is selectively and extensively phosphorylated at Ser129 in synucleinopathy lesions (PD, DLB, MSA); phosphorylation at Ser129 promotes fibril formation in vitro, identifying this modification as the dominant pathological post-translational modification. Mass spectrometry, phospho-specific antibody, in vitro fibril formation assay Nature cell biology High 11813001
2002 Mutant forms of α-synuclein associated with familial Parkinson's disease form annular protofibrils morphologically resembling pore-forming bacterial toxins, suggesting inappropriate membrane permeabilization as a pathogenic mechanism. Electron microscopy of recombinant protein assemblies, structural comparison Nature High 12124613
2003 Triplication (four copies) of the SNCA locus causes early-onset Parkinson's disease with dementia, establishing that increased gene dosage of wild-type α-synuclein alone is sufficient to cause disease. Genomic dosage analysis, FISH, linkage analysis in large kindred Science (New York, N.Y.) High 14593171
2004 The E46K mutation in SNCA causes autosomal dominant Parkinson's disease and Lewy body dementia; Lewy bodies in affected individuals are immunoreactive to α-synuclein and ubiquitin, establishing E46K as a third causative SNCA point mutation. SNCA gene sequencing, neuropathological examination, family co-segregation analysis Annals of neurology High 14755719
2004 Duplication of the SNCA locus causes familial Parkinson's disease with a clinical phenotype resembling idiopathic PD (late onset, slow progression, no prominent dementia), contrasting with the more severe triplication phenotype—establishing a gene dosage–phenotype relationship. Semiquantitative PCR, FISH in peripheral leukocytes, clinical characterization Lancet (London, England) High 15451224
2004 Wild-type α-synuclein is normally degraded via the chaperone-mediated autophagy (CMA) pathway; pathogenic A53T and A30P mutants bind the lysosomal CMA receptor but act as uptake blockers, inhibiting their own degradation and that of other CMA substrates. Lysosomal uptake assay, receptor-binding assay, in vitro CMA reconstitution Science (New York, N.Y.) High 15333840
2005 Extracellular aggregated α-synuclein activates microglia in primary mesencephalic neuron-glia cultures; microglial activation enhances dopaminergic neurodegeneration through phagocytosis of α-synuclein and NADPH oxidase-dependent reactive oxygen species production. Primary mesencephalic culture, microglial phagocytosis assay, NADPH oxidase inhibition, dopaminergic neuron counting FASEB journal High 15791003
2005 α-Synuclein immunoreactive inclusions are present in neurons of the gastric submucosal Meissner plexus and myenteric Auerbach plexus in individuals staged for PD-related brain pathology, suggesting enteric nervous system involvement and a possible route for pathogen-induced α-synuclein misfolding spreading from gut to brain. Immunocytochemistry on cryosections and paraffin sections of gastric tissue, staging correlation Neuroscience letters Medium 16330147
2006 α-Synuclein accumulation in yeast causes an early block in ER-to-Golgi vesicular trafficking; a genome-wide screen identified Rab GTPase Ypt1p (mammalian Rab1) as the key modifier; overexpression of Rab1 protected against α-synuclein-induced dopaminergic neuron loss in C. elegans and rat neuron models. Yeast genome-wide modifier screen, ER-to-Golgi trafficking assay, C. elegans dopaminergic neuron counting, rat neuron culture Science (New York, N.Y.) High 16794039
2006 Comprehensive inventory of α-synuclein modifications in Lewy bodies revealed that Ser129 phosphorylation is the predominant modification; ubiquitination occurs at Lys12, 21, and 23 and specific C-terminal truncations at Asp115, Asp119, Asn122, Tyr133, Asp135; ubiquitination appears secondary to phosphorylation and deposition. 2D immunoblot, sandwich ELISA with modification-specific antibodies, tandem mass spectrometry The Journal of biological chemistry High 16847063
2008 Patients homozygous for SNCA duplication show earlier onset and more severe cognitive impairment than heterozygotes, and biochemical analysis demonstrates that phosphorylated α-synuclein accumulates in the sarkosyl-insoluble urea-extracted fraction of brain, establishing a gene dosage–phosphorylation–aggregation relationship. Quantitative PCR for gene dosage, immunoblot of brain fractions, clinical characterization Archives of neurology Medium 18413475
2009 α-Synuclein is transmitted from affected neurons to neighboring neurons and to engrafted neuronal precursor cells via endocytosis, forming Lewy-like inclusions in recipient cells; lysosomal dysfunction promotes accumulation of transmitted α-synuclein; recipient cells show apoptotic markers (nuclear fragmentation, caspase 3 activation). Co-culture transmission assay, endocytosis inhibition, transgenic mouse model grafting, caspase activity assay Proceedings of the National Academy of Sciences of the United States of America High 19651612
2010 α-Synuclein directly binds the SNARE protein synaptobrevin-2/VAMP2 and promotes SNARE-complex assembly; triple-knockout mice lacking all synucleins develop age-dependent neurological impairments with decreased SNARE-complex assembly, establishing α-synuclein as a non-classical chaperone for SNARE-complex assembly. Recombinant protein binding assay, in vitro SNARE-complex assembly assay, triple-knockout mouse phenotyping, brain biochemistry Science (New York, N.Y.) High 20798282
2011 Endogenous α-synuclein isolated under non-denaturing conditions from neuronal and non-neuronal cell lines, brain tissue, and living human cells exists predominantly as a helically folded tetramer (~58 kDa); unlike recombinant monomers, native tetramers show α-helical structure without lipid addition, have greater lipid-binding capacity, and undergo little amyloid-like aggregation—suggesting that tetramer destabilization precedes pathological aggregation. Analytical ultracentrifugation, scanning transmission EM, in vivo crosslinking, CD spectroscopy, in vitro aggregation assay Nature High 21841800
2011 Functional loss of GD-linked glucocerebrosidase (GCase) in primary neurons and human iPSC-derived neurons causes lysosomal degradation impairment and α-synuclein accumulation; GCase substrate glucosylceramide (GlcCer) directly stabilizes soluble oligomeric α-synuclein intermediates in vitro; conversely, α-synuclein inhibits normal GCase lysosomal activity, forming a bidirectional pathogenic feedback loop. iPSC-derived neuron culture, in vitro GlcCer–α-synuclein aggregation assay, GCase activity assay in PD brain Cell High 21700325
2013 ABL1 tyrosine kinase is activated in PD brains and by lentiviral SNCA expression in mouse substantia nigra; lentiviral Abl expression increases SNCA levels; ABL1 inhibition with nilotinib decreases ABL1 activity and facilitates autophagic clearance of SNCA, with subcellular fractionation showing movement of SNCA from autophagic vacuoles to lysosomes. Lentiviral gene transfer in mice, subcellular fractionation, nilotinib treatment, transgenic mouse model Autophagy Medium 23787811
2015 Loss of GBA function in neuroblastoma cells and rat striatum leads to SNCA accumulation via inhibition of autophagy; this is mediated through PPP2A (protein phosphatase 2A) inactivation via Tyr307 phosphorylation, which suppresses BECN1 expression; PPP2A activation with C2-ceramide or rapamycin reverses GBA knockdown-induced SNCA accumulation. siRNA knockdown, glucocerebrosidase inhibition, PPP2A activity assay, pharmacological rescue in neuroblastoma cells and rat striatum Autophagy Medium 26378614
2015 α-Synuclein assemblies of distinct conformational strains (oligomers, ribbons, fibrils) produce different histopathological and behavioral phenotypes after brain injection in rats; fibrils are the major toxic strain causing progressive motor impairment and cell death; ribbons produce a distinct phenotype with both PD and MSA traits; α-synuclein assemblies can cross the blood-brain barrier after intravenous injection and amplify in vivo. Intracerebral and intravenous injection of structurally defined α-synuclein assemblies, behavioral testing, neuropathology, in vivo amplification assay Nature High 26061766
2018 Targeted DNA methylation editing at SNCA intron 1 using a dCas9-DNMT3A lentiviral system causes fine-tuned downregulation of SNCA mRNA and protein in hiPSC-derived dopaminergic neurons from a PD patient with SNCA triplication; this reduction rescues disease-related cellular phenotypes including mitochondrial ROS production and reduced cell viability, establishing intron 1 DNA methylation as a regulator of SNCA transcription. CRISPR-dCas9-DNMT3A epigenome editing, hiPSC-derived dopaminergic neurons, qRT-PCR, Western blot, ROS assay, cell viability assay Molecular therapy High 30266652
2018 CRISPR/Cas9n-mediated deletion of the endogenous SNCA gene in human embryonic stem cells confers dose-dependent resistance to α-synuclein preformed fibril (PFF)-induced Lewy-like pathology (pS129-αSyn aggregates) in mDA neurons, demonstrating that endogenous SNCA is required for seeded aggregation. CRISPR/Cas9n gene editing, hESC differentiation to mDA neurons, PFF seeding assay, phospho-α-synuclein immunofluorescence The European journal of neuroscience High 30472757
2021 The novel SNCA A30G mutation causes familial PD; biophysical characterization shows A30G has a local effect on the intrinsically disordered structure of α-synuclein, slightly perturbs membrane binding, and promotes fibril formation in vitro. Whole exome sequencing, haplotype analysis, NMR/biophysical characterization of recombinant A30G αSyn, fibril formation assay Movement disorders Medium 33617693
2021 Piperine (PIP) promotes autophagy flux via P2RX4 activation in SNCA-overexpression PD models; tandem mass tag proteomics identified P2RX4 as the key mediator; PIP enhanced autophagosome-lysosome membrane fusion and degradation of pathological SNCA in SK-N-SH cells and Thy1-SNCA transgenic mice, attenuating olfactory and motor deficits. TMT proteomics, autophagy flux assay (mRFP-GFP-LC3), transgenic mouse behavioral testing, siRNA knockdown of P2RX4 Autophagy Medium 34092198
2021 SNCA triplication midbrain organoids derived from patient iPSCs exhibit elevated α-synuclein levels and age-dependent accumulation of oligomeric and phosphorylated α-synuclein in both neurons and glial cells, correlating with selective reduction in dopaminergic neuron numbers, establishing a 3D model of synucleinopathy. iPSC-derived midbrain organoids, CRISPR isogenic correction, phospho-α-synuclein immunofluorescence, dopaminergic neuron quantification Brain communications Medium 34632384
2022 Recombinant human pro-CTSD (cathepsin D) is endocytosed by neuronal cells, targeted to lysosomes, and matured to active protease; application to iPSC-derived dopaminergic neurons from PD patients with SNCA A53T mutation reduces insoluble SNCA; in ctsd-knockout mouse neurons and brain, rHsCTSD decreases pathological SNCA conformers and restores endo-lysosomal and autophagy function, establishing CTSD as a critical lysosomal protease for SNCA clearance. Enzyme replacement in iPSC-derived neurons and ctsd-KO mice, SIM, immunofluorescence, Western blot fractionation, lysosomal targeting assay Autophagy High 35287553
2022 Macroautophagy and CMA are the primary degradation pathways for endogenous oligodendroglial SNCA and TPPP/p25A; TPPP/p25A contains a KFERQ-like motif enabling CMA degradation; in MSA-like settings with PFF seeding, PFF treatment impairs autophagic flux, TPPP/p25A inhibits macroautophagy, and CMA is upregulated to compensate; augmenting CMA or macroautophagy accelerates removal of pathological SNCA assemblies. siRNA knockdown of ATG5/LAMP2A, pharmacological modulation (rapamycin, AR7, 3-MA), lysosomal CMA assay with rat brain lysosomes, PFF seeding in oligodendroglial cells Autophagy Medium 35000546
2023 A 21-nucleotide duplication in SNCA (inserting MAAAEKT after residue 22, producing a 147-aa protein) causes juvenile-onset synucleinopathy; cryo-EM of sarkosyl-insoluble filaments from patient brain revealed a novel JOS α-synuclein fold (residues 36–100 as compact core, two disconnected density islands of mixed sequences, non-proteinaceous cofactor between core and island A) distinct from Lewy body disease and MSA folds; in vitro assembly of recombinant proteins yielded structures distinct from JOS filaments. Cryo-EM structure determination, genetic sequencing, in vitro fibril assembly, MS Acta neuropathologica High 36847833
2017 Blood RNA profiling of a SNCA gene duplication (PARK4) family revealed that CPLX1 (complexin 1) mRNA is inversely correlated with SNCA levels; SNCA gain of function impairs stimulus-triggered platelet degranulation; SNCA and CPLX1 mRNAs show inverse mutual regulation, and a CPLX1 3'-UTR SNP is significantly associated with PD risk. RNA-seq profiling of blood, platelet degranulation assay, qRT-PCR validation, genetic association analysis Disease models & mechanisms Medium 28108469
2019 SNCA multiplication (triplication) exacerbates neuronal nuclear aging: hiPSC-derived dopaminergic neurons from SNCA triplication patients show advanced aging signatures (altered heterochromatin, nuclear envelope markers, DNA damage, global DNA methylation) at juvenile stage; aged SNCA triplication neurons exhibit more α-synuclein aggregates per cell versus isogenic controls. hiPSC-derived neuron aging model (serial passaging of NPCs), immunofluorescence for heterochromatin/nuclear envelope markers, DNA damage assay, global DNA methylation analysis Human molecular genetics Medium 30304516

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science (New York, N.Y.) 6605 9197268
2014 PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 5424 25428505
2008 PD-1 and its ligands in tolerance and immunity. Annual review of immunology 4338 18173375
2003 alpha-Synuclein locus triplication causes Parkinson's disease. Science (New York, N.Y.) 3495 14593171
1998 Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nature genetics 3181 9462735
2016 Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. The New England journal of medicine 2538 27433843
2010 PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nature cell biology 2356 20098416
2004 The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Annals of neurology 2183 14755719
2010 The PD-1 pathway in tolerance and autoimmunity. Immunological reviews 1847 20636820
2002 alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nature cell biology 1744 11813001
2004 Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science (New York, N.Y.) 1632 15333840
2004 Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet (London, England) 1632 15451224
2018 Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. The New England journal of medicine 1605 29658848
2009 Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nature genetics 1562 19915575
2014 Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nature genetics 1512 25064009
2017 The diverse functions of the PD1 inhibitory pathway. Nature reviews. Immunology 1508 28990585
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2010 Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science (New York, N.Y.) 1445 20798282
2013 The role of oxidative stress in Parkinson's disease. Journal of Parkinson's disease 1396 24252804
1996 NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded. Biochemistry 1293 8901511
1993 Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America 1232 8248242
2009 Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proceedings of the National Academy of Sciences of the United States of America 1185 19651612
2006 Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. The Journal of biological chemistry 1161 16847063
2019 Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Molecular cancer 1144 30646912
2011 Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 1126 21700325
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2006 Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science (New York, N.Y.) 1113 16794039
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2009 Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nature genetics 1077 19915576
2005 Gastric alpha-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology. Neuroscience letters 1051 16330147
2002 Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 1048 12124613
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