{"gene":"SNCAIP","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":1999,"finding":"Synphilin-1 (SNCAIP) physically interacts with alpha-synuclein in vivo in neurons, as identified by yeast two-hybrid screen and confirmed by co-immunoprecipitation. Co-transfection of both proteins in HEK 293 cells yields cytoplasmic eosinophilic inclusions resembling Lewy bodies, while transfection of either protein alone does not.","method":"Yeast two-hybrid screen, co-immunoprecipitation from neurons, co-transfection in HEK 293 cells","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction confirmed in yeast two-hybrid and in vivo co-IP in neurons, functional inclusion formation in mammalian cells; foundational study replicated broadly","pmids":["10319874"],"is_preprint":false},{"year":2006,"finding":"Synphilin-1A, an isoform encoded by the SNCAIP gene with a different exon organization and translation start, binds alpha-synuclein and induces intracellular aggregate formation in HEK 293 cells, primary neuronal cultures, and human dopaminergic cells. Overexpression of synphilin-1A causes neuronal toxicity that is attenuated by the formation of synphilin-1A inclusions which recruit alpha-synuclein. Synphilin-1A is present in Lewy bodies of Parkinson's disease and Diffuse Lewy Body disease patients and in detergent-insoluble brain fractions.","method":"Molecular cloning, co-transfection assays, primary neuronal culture, human dopaminergic cell line overexpression, immunohistochemistry of patient tissue, detergent fractionation of brain samples","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (cell-based aggregation assays, neuronal toxicity assay, patient tissue validation, biochemical fractionation) in a single rigorous study","pmids":["16595633"],"is_preprint":false},{"year":2000,"finding":"The human SNCAIP gene is organized with its open reading frame contained within ten exons, maps to chromosome 5q23.1-23.3, and synphilin-1 protein is present in neuropil of human postmortem brain tissue, colocalizing with alpha-synuclein.","method":"Genomic cloning/sequencing, chromosomal mapping by genetic markers, immunohistochemistry of postmortem human brain","journal":"Mammalian genome : official journal of the International Mammalian Genome Society","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genomic and protein localization experiments, single lab, two orthogonal methods","pmids":["10967135"],"is_preprint":false},{"year":2004,"finding":"In vitro studies have linked synphilin-1 to ubiquitin-mediated protein degradation and identified novel synphilin-1-interacting proteins; the R621C mutation in SNCAIP was identified as a susceptibility factor for Parkinson's disease in two German patients.","method":"Review summarizing in vitro interaction and degradation studies; genetic variant identification","journal":"Cell and tissue research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review article summarizing prior in vitro work without providing primary experimental detail in the abstract","pmids":["15322916"],"is_preprint":false},{"year":2021,"finding":"In yeast models (S. cerevisiae and S. pombe), disruption of the glyoxalase system (lack of Glo2) and aldose reductase (Gre3) activity increases formation of large Synphilin-1 inclusions, correlating with enhanced oxidative stress and inhibition of exponential growth, likely caused by deregulation of autophagic degradation. This demonstrates that oxidation and glycation promote Synphilin-1 aggregation and toxicity.","method":"Expression of fluorescent dsRed-tagged or non-tagged human SNCAIP in yeast strains deleted for Glo1, Glo2, and Gre3; growth assays; fluorescence microscopy; oxidative stress measurements","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic deletion yeast model with multiple readouts (inclusion formation, growth, oxidative stress), single lab","pmids":["33562355"],"is_preprint":false},{"year":2015,"finding":"Porcine synphilin-1 (SNCAIP) encodes a 919-amino acid protein with 90% similarity to human synphilin-1. Three splice variants were identified that lack one or more exons, and all isoforms encoded by these variants lack functional domains important for protein degradation.","method":"RT-PCR cloning, cDNA sequencing, RNAseq expression analysis, domain analysis","journal":"Meta gene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — molecular cloning and sequence characterization, single lab, no functional validation of domain loss","pmids":["26101749"],"is_preprint":false},{"year":2023,"finding":"Expression of human Synphilin-1 in serotonergic and/or dopaminergic neurons of Drosophila melanogaster induces neurodegeneration and PD-like motor and non-motor symptoms. Olfactory and visual symptoms are primarily contributed by the serotonergic system, motor symptoms and reduced survival are mainly contributed by the dopaminergic system. Chronic nicotine treatment suppresses several of these phenotypes.","method":"Cell-type-specific transgenic expression in Drosophila, behavioral assays (motor, olfactory, visual), survival analysis, nicotine treatment","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via cell-type-specific expression in Drosophila with multiple behavioral readouts, single lab","pmids":["36857384"],"is_preprint":false}],"current_model":"Synphilin-1 (SNCAIP) is a multi-exon cytoplasmic protein that directly interacts with alpha-synuclein in neurons; co-expression of the two proteins drives formation of cytoplasmic eosinophilic inclusions resembling Lewy bodies, an aggregation-prone isoform (synphilin-1A) enhances this process and causes neuronal toxicity that is attenuated by inclusion formation, synphilin-1 is linked to ubiquitin-mediated protein degradation, and its aggregation propensity is increased by oxidation and glycation, collectively implicating SNCAIP in the pathogenesis of Parkinson's disease and related alpha-synucleinopathies."},"narrative":{"mechanistic_narrative":"Synphilin-1 (SNCAIP) is a cytoplasmic neuronal protein that functions as a direct binding partner of alpha-synuclein and a contributor to the formation of Lewy body-like cytoplasmic inclusions characteristic of alpha-synucleinopathies [PMID:10319874, PMID:16595633]. The protein was identified through its physical interaction with alpha-synuclein, and co-expression of the two proteins—neither sufficient alone—drives the formation of eosinophilic cytoplasmic inclusions in mammalian cells, with synphilin-1 colocalizing with alpha-synuclein in human brain neuropil [PMID:10319874, PMID:10967135]. An aggregation-prone isoform, synphilin-1A, encoded from the same gene through alternative exon organization and translation start, binds alpha-synuclein, drives intracellular aggregation, and is present in Lewy bodies and detergent-insoluble brain fractions of Parkinson's disease and Diffuse Lewy Body disease patients; the neuronal toxicity it produces is attenuated when its inclusions sequester alpha-synuclein, indicating inclusion formation is a protective response to a toxic soluble species [PMID:16595633]. Synphilin-1 aggregation and toxicity are promoted by oxidation and glycation, as loss of the glyoxalase and aldose reductase detoxification systems in yeast enhances inclusion formation alongside oxidative stress and impaired autophagic clearance [PMID:33562355], and neuronal expression of synphilin-1 in Drosophila produces dopaminergic and serotonergic neurodegeneration with Parkinson-like motor and non-motor phenotypes [PMID:36857384]. Beyond its link to ubiquitin-mediated protein degradation [PMID:15322916], the enzymatic and structural mechanism of synphilin-1 has not been characterized in the available corpus.","teleology":[{"year":1999,"claim":"Establishing that synphilin-1 is a physical partner of alpha-synuclein answered whether alpha-synuclein has dedicated neuronal interactors that could nucleate the inclusions seen in Parkinson's disease.","evidence":"Yeast two-hybrid screen, in vivo co-immunoprecipitation from neurons, and co-transfection inclusion assay in HEK 293 cells","pmids":["10319874"],"confidence":"High","gaps":["Binding interface and stoichiometry of the synphilin-1/alpha-synuclein complex not defined","Whether inclusion formation is protective or pathogenic not resolved by this study","No endogenous neuronal function assigned"]},{"year":2000,"claim":"Genomic characterization fixed the gene structure and chromosomal location and confirmed that endogenous synphilin-1 protein colocalizes with alpha-synuclein in human brain, anchoring the interaction in native tissue.","evidence":"Genomic cloning/sequencing, chromosomal mapping, and immunohistochemistry of postmortem human brain","pmids":["10967135"],"confidence":"Medium","gaps":["No functional domain mapping","Subcellular compartment within neurons not specified"]},{"year":2004,"claim":"Linking synphilin-1 to ubiquitin-mediated degradation and identifying a disease-associated R621C variant connected the protein to protein turnover pathways and to PD susceptibility.","evidence":"Review summarizing in vitro interaction/degradation studies and genetic variant identification in two patients","pmids":["15322916"],"confidence":"Low","gaps":["Review-level summary without primary experimental detail in abstract","R621C causality not established beyond two-patient association","Specific E3 ligase/proteasome mechanism not defined"]},{"year":2006,"claim":"Discovery of the synphilin-1A isoform clarified that an alternatively organized transcript of the same gene is the aggregation-prone, disease-relevant species, and that inclusion formation buffers its intrinsic toxicity.","evidence":"Molecular cloning, co-transfection and neuronal toxicity assays, patient tissue immunohistochemistry, and detergent fractionation of brain","pmids":["16595633"],"confidence":"High","gaps":["Molecular determinant making synphilin-1A more aggregation-prone than synphilin-1 not identified","Mechanism by which inclusions reduce toxicity unresolved","Relative in vivo abundance of the two isoforms unknown"]},{"year":2021,"claim":"Yeast genetics established that oxidative and glycation stress, via the glyoxalase and aldose reductase systems and autophagy, are upstream modulators of synphilin-1 aggregation and toxicity.","evidence":"Expression of human SNCAIP in Glo1/Glo2/Gre3-deletion yeast with inclusion imaging, growth, and oxidative stress readouts","pmids":["33562355"],"confidence":"Medium","gaps":["Direct sites of oxidation/glycation on synphilin-1 not mapped","Relevance of yeast autophagy link to neuronal clearance not demonstrated","Single-lab model"]},{"year":2023,"claim":"Cell-type-specific expression in Drosophila demonstrated that synphilin-1 is sufficient to drive neurodegeneration and Parkinson-like phenotypes in vivo, with distinct dopaminergic and serotonergic contributions.","evidence":"Transgenic neuron-type-specific expression in Drosophila with motor/olfactory/visual behavioral assays, survival analysis, and nicotine treatment","pmids":["36857384"],"confidence":"Medium","gaps":["Molecular pathway linking synphilin-1 expression to neuronal death not defined","Role of endogenous fly alpha-synuclein ortholog absent","Mechanism of nicotine rescue unknown"]},{"year":null,"claim":"The normal cellular function of synphilin-1 and the biochemical mechanism by which it engages ubiquitin-mediated degradation remain undefined, as does the structural basis of its alpha-synuclein binding and aggregation.","evidence":"No discovery in the corpus assigns an endogenous enzymatic or structural function","pmids":[],"confidence":"Low","gaps":["No catalytic activity established","No structure of synphilin-1 or its complexes","Physiological (non-disease) role unknown"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,2]}],"pathway":[],"complexes":[],"partners":["SNCA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y6H5","full_name":"Synphilin-1","aliases":["Alpha-synuclein-interacting protein"],"length_aa":919,"mass_kda":100.4,"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","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9Y6H5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SNCAIP","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SNCAIP","total_profiled":1310},"omim":[{"mim_id":"607207","title":"STIP1 HOMOLOGOUS AND U BOX-CONTAINING PROTEIN 1; STUB1","url":"https://www.omim.org/entry/607207"},{"mim_id":"604605","title":"KALIRIN; KALRN","url":"https://www.omim.org/entry/604605"},{"mim_id":"603779","title":"SYNUCLEIN-ALPHA-INTERACTING PROTEIN; SNCAIP","url":"https://www.omim.org/entry/603779"},{"mim_id":"300272","title":"HISTONE DEACETYLASE 6; HDAC6","url":"https://www.omim.org/entry/300272"},{"mim_id":"168600","title":"PARKINSON DISEASE, LATE-ONSET; PD","url":"https://www.omim.org/entry/168600"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytoplasmic bodies","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"cervix","ntpm":16.1},{"tissue":"endometrium 1","ntpm":18.2},{"tissue":"ovary","ntpm":24.6}],"url":"https://www.proteinatlas.org/search/SNCAIP"},"hgnc":{"alias_symbol":["SYPH1"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y6H5","domains":[{"cath_id":"1.25.40.20","chopping":"312-413","consensus_level":"medium","plddt":88.255,"start":312,"end":413},{"cath_id":"1.25.40.20","chopping":"416-521","consensus_level":"medium","plddt":93.4818,"start":416,"end":521}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6H5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6H5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6H5-F1-predicted_aligned_error_v6.png","plddt_mean":51.59},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNCAIP","jax_strain_url":"https://www.jax.org/strain/search?query=SNCAIP"},"sequence":{"accession":"Q9Y6H5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y6H5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y6H5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6H5"}},"corpus_meta":[{"pmid":"22832581","id":"PMC_22832581","title":"Subgroup-specific structural variation across 1,000 medulloblastoma genomes.","date":"2012","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/22832581","citation_count":729,"is_preprint":false},{"pmid":"10319874","id":"PMC_10319874","title":"Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions.","date":"1999","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10319874","citation_count":407,"is_preprint":false},{"pmid":"32048886","id":"PMC_32048886","title":"Organelle-specific autophagy in inflammatory diseases: a potential therapeutic target underlying the quality control of multiple organelles.","date":"2020","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/32048886","citation_count":347,"is_preprint":false},{"pmid":"25484190","id":"PMC_25484190","title":"Autophagy modulates SNCA/α-synuclein release, thereby generating a hostile microenvironment.","date":"2014","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/25484190","citation_count":186,"is_preprint":false},{"pmid":"24980887","id":"PMC_24980887","title":"Genome-wide DNA methylation study identifies significant epigenomic changes in osteoarthritic cartilage.","date":"2014","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/24980887","citation_count":117,"is_preprint":false},{"pmid":"34148545","id":"PMC_34148545","title":"Identification of sixteen novel candidate genes for late onset Parkinson's disease.","date":"2021","source":"Molecular neurodegeneration","url":"https://pubmed.ncbi.nlm.nih.gov/34148545","citation_count":70,"is_preprint":false},{"pmid":"23684749","id":"PMC_23684749","title":"Identification of candidate oncogenes in human colorectal cancers with microsatellite instability.","date":"2013","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/23684749","citation_count":60,"is_preprint":false},{"pmid":"23127794","id":"PMC_23127794","title":"Aberrant alternative splicing events in Parkinson's disease.","date":"2012","source":"Cell transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/23127794","citation_count":46,"is_preprint":false},{"pmid":"16595633","id":"PMC_16595633","title":"Synphilin-1A: an aggregation-prone isoform of synphilin-1 that causes neuronal death and is present in aggregates from alpha-synucleinopathy patients.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16595633","citation_count":44,"is_preprint":false},{"pmid":"28415684","id":"PMC_28415684","title":"The long noncoding RNA linc-NeD125 controls the expression of medulloblastoma driver genes by microRNA sponge activity.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28415684","citation_count":41,"is_preprint":false},{"pmid":"35489737","id":"PMC_35489737","title":"Molecular Stratification of Medulloblastoma: Clinical Outcomes and Therapeutic Interventions.","date":"2022","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/35489737","citation_count":33,"is_preprint":false},{"pmid":"25811964","id":"PMC_25811964","title":"Derivatives containing both coumarin and benzimidazole potently induce caspase-dependent apoptosis of cancer cells through inhibition of PI3K-AKT-mTOR signaling.","date":"2015","source":"Anti-cancer drugs","url":"https://pubmed.ncbi.nlm.nih.gov/25811964","citation_count":26,"is_preprint":false},{"pmid":"15322916","id":"PMC_15322916","title":"The role of synphilin-1 in synaptic function and protein degradation.","date":"2004","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/15322916","citation_count":24,"is_preprint":false},{"pmid":"27047539","id":"PMC_27047539","title":"Genome-Wide Study of Response to Platinum, Taxane, and Combination Therapy in Ovarian Cancer: In vitro Phenotypes, Inherited Variation, and Disease Recurrence.","date":"2016","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27047539","citation_count":24,"is_preprint":false},{"pmid":"26460308","id":"PMC_26460308","title":"Genome-Wide Association Study of Event-Free Survival in Diffuse Large B-Cell Lymphoma Treated With Immunochemotherapy.","date":"2015","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26460308","citation_count":22,"is_preprint":false},{"pmid":"10967135","id":"PMC_10967135","title":"Organization of the human synphilin-1 gene, a candidate for Parkinson's disease.","date":"2000","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/10967135","citation_count":21,"is_preprint":false},{"pmid":"30740043","id":"PMC_30740043","title":"Global Gene Knockout of Kcnip3 Enhances Pain Sensitivity and Exacerbates Negative Emotions in Rats.","date":"2019","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30740043","citation_count":15,"is_preprint":false},{"pmid":"21344240","id":"PMC_21344240","title":"Identification of Parkinson's disease candidate genes using CAESAR and screening of MAPT and SNCAIP in South African Parkinson's disease patients.","date":"2011","source":"Journal of neural transmission (Vienna, Austria : 1996)","url":"https://pubmed.ncbi.nlm.nih.gov/21344240","citation_count":14,"is_preprint":false},{"pmid":"28653979","id":"PMC_28653979","title":"Hypermethylation of Synphilin-1, Alpha-Synuclein-Interacting Protein (SNCAIP) Gene in the Cerebral Cortex of Patients with Sporadic Parkinson's Disease.","date":"2017","source":"Brain sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28653979","citation_count":13,"is_preprint":false},{"pmid":"14639662","id":"PMC_14639662","title":"Case-control study of the alpha-synuclein interacting protein gene and Parkinson's disease.","date":"2003","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/14639662","citation_count":13,"is_preprint":false},{"pmid":"33062672","id":"PMC_33062672","title":"Genomic Analysis Reveals Novel Specific Metastatic Mutations in Chinese Clear Cell Renal Cell Carcinoma.","date":"2020","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/33062672","citation_count":13,"is_preprint":false},{"pmid":"29268803","id":"PMC_29268803","title":"Genomic dissection and prediction of feed intake and residual feed intake traits using a longitudinal model in F2 chickens.","date":"2017","source":"Animal : an international journal of animal bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/29268803","citation_count":12,"is_preprint":false},{"pmid":"36857384","id":"PMC_36857384","title":"Parkinsonian phenotypes induced by Synphilin-1 expression are differentially contributed by serotonergic and dopaminergic circuits and suppressed by nicotine treatment.","date":"2023","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/36857384","citation_count":10,"is_preprint":false},{"pmid":"34573432","id":"PMC_34573432","title":"Genome-Wide Survey for Microdeletions or -Duplications in 155 Patients with Lower Urinary Tract Obstructions (LUTO).","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/34573432","citation_count":9,"is_preprint":false},{"pmid":"35633541","id":"PMC_35633541","title":"Antitumor Activity of Choerospondias axillaris Fruit Extract by Regulating the Expression of SNCAIP and SNCA on MDA-MB-231 Cells.","date":"2022","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/35633541","citation_count":8,"is_preprint":false},{"pmid":"41051722","id":"PMC_41051722","title":"Amyloid-β, Tau, and α-Synuclein Protein Interactomes as Therapeutic Targets in Neurodegenerative Diseases.","date":"2025","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/41051722","citation_count":6,"is_preprint":false},{"pmid":"31203147","id":"PMC_31203147","title":"Immune-related somatic mutation genes are enriched in PDACs with diabetes.","date":"2019","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31203147","citation_count":6,"is_preprint":false},{"pmid":"34445568","id":"PMC_34445568","title":"Distinctive Properties of Endothelial Cells from Tumor and Normal Tissue in Human Breast Cancer.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34445568","citation_count":6,"is_preprint":false},{"pmid":"39253064","id":"PMC_39253064","title":"Key Cell-in-Cell Related Genes are Identified by Bioinformatics and Experiments in Glioblastoma.","date":"2024","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/39253064","citation_count":4,"is_preprint":false},{"pmid":"41026459","id":"PMC_41026459","title":"Elucidate biomarkers and the molecular pathways associated with genetic variants that contribute to the etiology of Parkinson's disease.","date":"2025","source":"Acta neurologica Belgica","url":"https://pubmed.ncbi.nlm.nih.gov/41026459","citation_count":4,"is_preprint":false},{"pmid":"26101749","id":"PMC_26101749","title":"Splicing variants of porcine synphilin-1.","date":"2015","source":"Meta gene","url":"https://pubmed.ncbi.nlm.nih.gov/26101749","citation_count":2,"is_preprint":false},{"pmid":"39674535","id":"PMC_39674535","title":"Co-occurrence of Parkinson's disease and Retinitis Pigmentosa: A genetic and in silico analysis.","date":"2024","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/39674535","citation_count":2,"is_preprint":false},{"pmid":"33562355","id":"PMC_33562355","title":"Yeasts as Complementary Model Systems for the Study of the Pathological Repercussions of Enhanced Synphilin-1 Glycation and Oxidation.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33562355","citation_count":2,"is_preprint":false},{"pmid":"40556027","id":"PMC_40556027","title":"Robust molecular subgrouping and reference-free aneuploidy detection in medulloblastoma using low-depth whole genome bisulfite sequencing.","date":"2025","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/40556027","citation_count":1,"is_preprint":false},{"pmid":"41425758","id":"PMC_41425758","title":"Synergetic effect of taurine/taurine nanoparticles along with Sinemet® against rotenone-induced Parkinson's disease in mice.","date":"2025","source":"Toxicology research","url":"https://pubmed.ncbi.nlm.nih.gov/41425758","citation_count":1,"is_preprint":false},{"pmid":"40474964","id":"PMC_40474964","title":"Rare Copy Number Variants Intersecting Parkinson's-associated Genes in a Cohort of children With Autism Spectrum Disorders.","date":"2025","source":"Neuroscience insights","url":"https://pubmed.ncbi.nlm.nih.gov/40474964","citation_count":0,"is_preprint":false},{"pmid":"32568194","id":"PMC_32568194","title":"Mutation Analysis of the Genes Associated with Parkinson's Disease in a Finnish Cohort of Early-Onset Dementia.","date":"2020","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/32568194","citation_count":0,"is_preprint":false},{"pmid":"41658012","id":"PMC_41658012","title":"Identification of CTHRC1 as a novel candidate for neurodevelopmental disorders.","date":"2026","source":"Frontiers in aging neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/41658012","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23736,"output_tokens":1905,"usd":0.049891,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8793,"output_tokens":2463,"usd":0.05277,"stage2_stop_reason":"end_turn"},"total_usd":0.102661,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"Synphilin-1 (SNCAIP) physically interacts with alpha-synuclein in vivo in neurons, as identified by yeast two-hybrid screen and confirmed by co-immunoprecipitation. Co-transfection of both proteins in HEK 293 cells yields cytoplasmic eosinophilic inclusions resembling Lewy bodies, while transfection of either protein alone does not.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation from neurons, co-transfection in HEK 293 cells\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction confirmed in yeast two-hybrid and in vivo co-IP in neurons, functional inclusion formation in mammalian cells; foundational study replicated broadly\",\n      \"pmids\": [\"10319874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Synphilin-1A, an isoform encoded by the SNCAIP gene with a different exon organization and translation start, binds alpha-synuclein and induces intracellular aggregate formation in HEK 293 cells, primary neuronal cultures, and human dopaminergic cells. Overexpression of synphilin-1A causes neuronal toxicity that is attenuated by the formation of synphilin-1A inclusions which recruit alpha-synuclein. Synphilin-1A is present in Lewy bodies of Parkinson's disease and Diffuse Lewy Body disease patients and in detergent-insoluble brain fractions.\",\n      \"method\": \"Molecular cloning, co-transfection assays, primary neuronal culture, human dopaminergic cell line overexpression, immunohistochemistry of patient tissue, detergent fractionation of brain samples\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (cell-based aggregation assays, neuronal toxicity assay, patient tissue validation, biochemical fractionation) in a single rigorous study\",\n      \"pmids\": [\"16595633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The human SNCAIP gene is organized with its open reading frame contained within ten exons, maps to chromosome 5q23.1-23.3, and synphilin-1 protein is present in neuropil of human postmortem brain tissue, colocalizing with alpha-synuclein.\",\n      \"method\": \"Genomic cloning/sequencing, chromosomal mapping by genetic markers, immunohistochemistry of postmortem human brain\",\n      \"journal\": \"Mammalian genome : official journal of the International Mammalian Genome Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genomic and protein localization experiments, single lab, two orthogonal methods\",\n      \"pmids\": [\"10967135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In vitro studies have linked synphilin-1 to ubiquitin-mediated protein degradation and identified novel synphilin-1-interacting proteins; the R621C mutation in SNCAIP was identified as a susceptibility factor for Parkinson's disease in two German patients.\",\n      \"method\": \"Review summarizing in vitro interaction and degradation studies; genetic variant identification\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review article summarizing prior in vitro work without providing primary experimental detail in the abstract\",\n      \"pmids\": [\"15322916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In yeast models (S. cerevisiae and S. pombe), disruption of the glyoxalase system (lack of Glo2) and aldose reductase (Gre3) activity increases formation of large Synphilin-1 inclusions, correlating with enhanced oxidative stress and inhibition of exponential growth, likely caused by deregulation of autophagic degradation. This demonstrates that oxidation and glycation promote Synphilin-1 aggregation and toxicity.\",\n      \"method\": \"Expression of fluorescent dsRed-tagged or non-tagged human SNCAIP in yeast strains deleted for Glo1, Glo2, and Gre3; growth assays; fluorescence microscopy; oxidative stress measurements\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic deletion yeast model with multiple readouts (inclusion formation, growth, oxidative stress), single lab\",\n      \"pmids\": [\"33562355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Porcine synphilin-1 (SNCAIP) encodes a 919-amino acid protein with 90% similarity to human synphilin-1. Three splice variants were identified that lack one or more exons, and all isoforms encoded by these variants lack functional domains important for protein degradation.\",\n      \"method\": \"RT-PCR cloning, cDNA sequencing, RNAseq expression analysis, domain analysis\",\n      \"journal\": \"Meta gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — molecular cloning and sequence characterization, single lab, no functional validation of domain loss\",\n      \"pmids\": [\"26101749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Expression of human Synphilin-1 in serotonergic and/or dopaminergic neurons of Drosophila melanogaster induces neurodegeneration and PD-like motor and non-motor symptoms. Olfactory and visual symptoms are primarily contributed by the serotonergic system, motor symptoms and reduced survival are mainly contributed by the dopaminergic system. Chronic nicotine treatment suppresses several of these phenotypes.\",\n      \"method\": \"Cell-type-specific transgenic expression in Drosophila, behavioral assays (motor, olfactory, visual), survival analysis, nicotine treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via cell-type-specific expression in Drosophila with multiple behavioral readouts, single lab\",\n      \"pmids\": [\"36857384\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Synphilin-1 (SNCAIP) is a multi-exon cytoplasmic protein that directly interacts with alpha-synuclein in neurons; co-expression of the two proteins drives formation of cytoplasmic eosinophilic inclusions resembling Lewy bodies, an aggregation-prone isoform (synphilin-1A) enhances this process and causes neuronal toxicity that is attenuated by inclusion formation, synphilin-1 is linked to ubiquitin-mediated protein degradation, and its aggregation propensity is increased by oxidation and glycation, collectively implicating SNCAIP in the pathogenesis of Parkinson's disease and related alpha-synucleinopathies.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Synphilin-1 (SNCAIP) is a cytoplasmic neuronal protein that functions as a direct binding partner of alpha-synuclein and a contributor to the formation of Lewy body-like cytoplasmic inclusions characteristic of alpha-synucleinopathies [#0, #1]. The protein was identified through its physical interaction with alpha-synuclein, and co-expression of the two proteins—neither sufficient alone—drives the formation of eosinophilic cytoplasmic inclusions in mammalian cells, with synphilin-1 colocalizing with alpha-synuclein in human brain neuropil [#0, #2]. An aggregation-prone isoform, synphilin-1A, encoded from the same gene through alternative exon organization and translation start, binds alpha-synuclein, drives intracellular aggregation, and is present in Lewy bodies and detergent-insoluble brain fractions of Parkinson's disease and Diffuse Lewy Body disease patients; the neuronal toxicity it produces is attenuated when its inclusions sequester alpha-synuclein, indicating inclusion formation is a protective response to a toxic soluble species [#1]. Synphilin-1 aggregation and toxicity are promoted by oxidation and glycation, as loss of the glyoxalase and aldose reductase detoxification systems in yeast enhances inclusion formation alongside oxidative stress and impaired autophagic clearance [#4], and neuronal expression of synphilin-1 in Drosophila produces dopaminergic and serotonergic neurodegeneration with Parkinson-like motor and non-motor phenotypes [#6]. Beyond its link to ubiquitin-mediated protein degradation [#3], the enzymatic and structural mechanism of synphilin-1 has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that synphilin-1 is a physical partner of alpha-synuclein answered whether alpha-synuclein has dedicated neuronal interactors that could nucleate the inclusions seen in Parkinson's disease.\",\n      \"evidence\": \"Yeast two-hybrid screen, in vivo co-immunoprecipitation from neurons, and co-transfection inclusion assay in HEK 293 cells\",\n      \"pmids\": [\"10319874\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface and stoichiometry of the synphilin-1/alpha-synuclein complex not defined\", \"Whether inclusion formation is protective or pathogenic not resolved by this study\", \"No endogenous neuronal function assigned\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Genomic characterization fixed the gene structure and chromosomal location and confirmed that endogenous synphilin-1 protein colocalizes with alpha-synuclein in human brain, anchoring the interaction in native tissue.\",\n      \"evidence\": \"Genomic cloning/sequencing, chromosomal mapping, and immunohistochemistry of postmortem human brain\",\n      \"pmids\": [\"10967135\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional domain mapping\", \"Subcellular compartment within neurons not specified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linking synphilin-1 to ubiquitin-mediated degradation and identifying a disease-associated R621C variant connected the protein to protein turnover pathways and to PD susceptibility.\",\n      \"evidence\": \"Review summarizing in vitro interaction/degradation studies and genetic variant identification in two patients\",\n      \"pmids\": [\"15322916\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Review-level summary without primary experimental detail in abstract\", \"R621C causality not established beyond two-patient association\", \"Specific E3 ligase/proteasome mechanism not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Discovery of the synphilin-1A isoform clarified that an alternatively organized transcript of the same gene is the aggregation-prone, disease-relevant species, and that inclusion formation buffers its intrinsic toxicity.\",\n      \"evidence\": \"Molecular cloning, co-transfection and neuronal toxicity assays, patient tissue immunohistochemistry, and detergent fractionation of brain\",\n      \"pmids\": [\"16595633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular determinant making synphilin-1A more aggregation-prone than synphilin-1 not identified\", \"Mechanism by which inclusions reduce toxicity unresolved\", \"Relative in vivo abundance of the two isoforms unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Yeast genetics established that oxidative and glycation stress, via the glyoxalase and aldose reductase systems and autophagy, are upstream modulators of synphilin-1 aggregation and toxicity.\",\n      \"evidence\": \"Expression of human SNCAIP in Glo1/Glo2/Gre3-deletion yeast with inclusion imaging, growth, and oxidative stress readouts\",\n      \"pmids\": [\"33562355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct sites of oxidation/glycation on synphilin-1 not mapped\", \"Relevance of yeast autophagy link to neuronal clearance not demonstrated\", \"Single-lab model\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cell-type-specific expression in Drosophila demonstrated that synphilin-1 is sufficient to drive neurodegeneration and Parkinson-like phenotypes in vivo, with distinct dopaminergic and serotonergic contributions.\",\n      \"evidence\": \"Transgenic neuron-type-specific expression in Drosophila with motor/olfactory/visual behavioral assays, survival analysis, and nicotine treatment\",\n      \"pmids\": [\"36857384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway linking synphilin-1 expression to neuronal death not defined\", \"Role of endogenous fly alpha-synuclein ortholog absent\", \"Mechanism of nicotine rescue unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The normal cellular function of synphilin-1 and the biochemical mechanism by which it engages ubiquitin-mediated degradation remain undefined, as does the structural basis of its alpha-synuclein binding and aggregation.\",\n      \"evidence\": \"No discovery in the corpus assigns an endogenous enzymatic or structural function\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No catalytic activity established\", \"No structure of synphilin-1 or its complexes\", \"Physiological (non-disease) role unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"SNCA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":4,"faith_total":4,"faith_pct":100.0}}