{"gene":"DNAJC6","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2012,"finding":"DNAJC6 encodes the neuronal HSP40 co-chaperone auxilin, which confers specificity to the ATPase activity of Hsc70 in clathrin uncoating. Loss-of-function mutations in DNAJC6 cause abnormal retention of assembled clathrin on synaptic vesicles and in empty cages, leading to impaired synaptic vesicle recycling and perturbed clathrin-mediated endocytosis in neurons. Non-neuronal cells are unaffected because a different J-domain-containing partner compensates for auxilin in co-chaperoning Hsc70-mediated uncoating activity.","method":"Homozygosity mapping, whole exome sequencing, transferrin uptake endocytosis assay in patient fibroblasts, mRNA level analysis; prior auxilin null mouse data cited","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional endocytosis assay in patient cells plus cited null-mouse model; single lab but two orthogonal methods","pmids":["22563501"],"is_preprint":false},{"year":2016,"finding":"Homozygous DNAJC6 mutations cause severely decreased steady-state levels of the auxilin protein in patient fibroblasts, confirming loss-of-function as the pathogenic mechanism in early-onset Parkinson's disease.","method":"Protein studies (Western blot) in patient-derived fibroblasts, cosegregation analysis, whole-exome sequencing","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein quantification in patient fibroblasts, replicated across two independent families","pmids":["26528954"],"is_preprint":false},{"year":2020,"finding":"DNAJC6/auxilin deficiency in patients results in disrupted dopamine homeostasis, evidenced by isolated reduction of homovanillic acid in CSF, reduced presynaptic dopaminergic proteins, and significantly reduced auxilin levels in both fibroblasts and CSF. Cyclin G-associated kinase (GAK) levels in CSF were significantly increased, suggesting a compensatory upregulation of GAK upon auxilin loss, consistent with observations in the auxilin knockout mouse.","method":"CSF neurotransmitter analysis, Western blot of patient fibroblasts and CSF for auxilin and GAK, DaTScan (123I-FP-CIT SPECT), whole-exome sequencing","journal":"Movement disorders : official journal of the Movement Disorder Society","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (biochemical CSF analysis, protein quantification, neuroimaging) in patient cohort, single lab","pmids":["32472658"],"is_preprint":false},{"year":2021,"finding":"DNAJC6 mutations in human midbrain-like organoids cause degeneration of midbrain-type dopamine neurons, pathologic α-synuclein aggregation, increased intrinsic neuronal firing frequency, and mitochondrial and lysosomal dysfunctions. Mechanistically, DNAJC6-mediated endocytosis defects impair the WNT-LMX1A signaling pathway during midbrain dopamine neuron development, and reduced LMX1A expression generates vulnerable neurons with pathologic manifestations.","method":"CRISPR-Cas9 gene editing of human embryonic stem cells, human midbrain-like organoids (hMLOs), transcriptomic analyses, experimental validation of WNT-LMX1A signaling pathway","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR loss-of-function with multiple orthogonal readouts and pathway validation in human organoid model, single lab","pmids":["33597231"],"is_preprint":false},{"year":2023,"finding":"In a Drosophila knock-in model of DNAJC6/Auxilin pathogenic mutation, loss of auxilin causes synaptic dysfunction, neurological defects, neurodegeneration, and specific lipid metabolism alterations including reduction of membrane phosphatidylinositol lipid species containing long-chain polyunsaturated fatty acids. Overexpression of Synaptojanin-1 (SYNJ1), which binds and metabolizes phosphoinositides, rescues the DNAJC6/Auxilin lipid alterations, neuronal function defects, and neurodegeneration, establishing a functional relationship between auxilin and SYNJ1 through phosphoinositide metabolism.","method":"Drosophila knock-in model, lipidomics, genetic rescue by Synaptojanin-1 overexpression, neurological/behavioral assays, neurodegeneration readouts","journal":"NPJ Parkinson's disease","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo knock-in model with lipidomics plus genetic epistasis rescue, multiple orthogonal methods establishing pathway relationship","pmids":["36739293"],"is_preprint":false},{"year":2024,"finding":"In iPSC-derived midbrain dopaminergic neurons from DNAJC6 loss-of-function patients, auxilin deficiency disturbs synaptic vesicle recycling and homeostasis, and causes neurodevelopmental dysregulation affecting ventral midbrain patterning and neuronal maturation. Lentiviral DNAJC6 gene transfer restored auxilin expression and rescued clathrin-mediated endocytosis, directly confirming that auxilin is required for CME at the presynaptic terminal.","method":"iPSC generation from patients, CRISPR-corrected isogenic controls, lentiviral gene transfer rescue, functional CME assays, synaptic vesicle recycling assays","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — gene transfer rescue with functional CME assay in isogenic-controlled patient-derived neurons, multiple orthogonal methods","pmids":["38242634"],"is_preprint":false},{"year":2024,"finding":"DNAJC6 paucity in differentiated human SH-SY5Y dopaminergic neurons reduces cytosolic clathrin heavy chain levels and lysosomal number, which downregulates lysosomal cathepsin D and impairs macroautophagy, leading to upregulation of pathologic α-synuclein (including phospho-α-synuclein Ser129) in the ER and mitochondria. ER α-synuclein accumulation activates ER stress, the unfolded protein response, and apoptotic signaling; mitochondrial α-synuclein depolarizes mitochondrial membrane potential and increases superoxide. Knockdown of α-synuclein or cathepsin D blocked DNAJC6 deficiency-evoked dopaminergic cell degeneration. PARK19 DNAJC6 mutants (Q789X or R927G) failed to attenuate tunicamycin- or rotenone-induced upregulation of pathologic α-synuclein and apoptotic signaling, unlike WT DNAJC6.","method":"shRNA-mediated gene silencing in differentiated SH-SY5Y neurons, lysosome quantification, cathepsin D assay, α-synuclein immunofluorescence, mitochondrial membrane potential measurement, superoxide assay, ER stress markers, mutant protein rescue experiments","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in cell model with both KD and mutant expression, single lab","pmids":["38928416"],"is_preprint":false},{"year":2026,"finding":"In a PARK19 knock-in mouse model (Dnajc6Q787X/Q787X), truncated Dnajc6 decreases clathrin heavy chain and lysosomal number in substantia nigra dopaminergic neurons, leading to downregulation of lysosomal cathepsin D and upregulation of α-synuclein and α-synuclein oligomers, ER stress, mitochondrial apoptotic cascades, microglial NLRP3 inflammasome activation, and neuroinflammatory cell death cascades (RIPK1-RIPK3-MLKL). Rapamycin (lysosomal biogenesis activator) precluded cathepsin D downregulation, α-synuclein upregulation, and PARK19 phenotypes, confirming the causal lysosomal-cathepsin D axis.","method":"PARK19 knock-in mouse model, rapamycin pharmacological rescue, immunohistochemistry, lysosome/cathepsin D quantification, α-synuclein/oligomer detection, NLRP3 inflammasome markers, death cascade protein analysis","journal":"NPJ Parkinson's disease","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo knock-in mouse model with pharmacological rescue and multiple orthogonal mechanistic readouts","pmids":["41820376"],"is_preprint":false},{"year":2026,"finding":"DNAJC6 expression in the substantia nigra is regulated transcriptionally by the midbrain-specific factors NURR1 and FOXA2, and protein stability is regulated by LRRK2. In astrocytes, DNAJC6 deficiency impairs phagocytic, autolysosomal, and mitochondrial functions while promoting a proinflammatory phenotype. CRISPRa-AAV9-mediated epigenetic restoration of DNAJC6 in neurons and astrocytes in an α-synuclein-induced mouse PD model alleviated behavioral deficits and neuropathology.","method":"Postmortem tissue analysis, hPSC-derived midbrain cultures, mechanistic studies of NURR1/FOXA2 transcriptional regulation, LRRK2-mediated protein stability assays, astrocyte functional assays (phagocytosis, autolysosomal, mitochondrial), CRISPRa-AAV9 in vivo gene activation","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including in vivo rescue; mechanistic claims about NURR1/FOXA2 and LRRK2 from single lab, some aspects rely on abstract-level reporting","pmids":["41955024"],"is_preprint":false}],"current_model":"DNAJC6 encodes auxilin, a neuronal HSP40 co-chaperone that activates Hsc70 ATPase activity to drive clathrin uncoating during clathrin-mediated endocytosis (CME) at the presynaptic terminal; loss of auxilin impairs synaptic vesicle recycling, reduces clathrin heavy chain and lysosomal number, disrupts phosphoinositide and lipid homeostasis (functionally linked to Synaptojanin-1), downregulates lysosomal cathepsin D, and causes pathologic α-synuclein accumulation with ER stress, mitochondrial dysfunction, and neuroinflammatory cell death cascades leading to dopaminergic neuron degeneration; auxilin transcription is controlled by NURR1/FOXA2 and its protein stability is regulated by LRRK2, while GAK compensates for auxilin loss in non-neuronal cells."},"narrative":{"mechanistic_narrative":"DNAJC6 encodes auxilin, a neuronal HSP40 co-chaperone that confers substrate specificity to the ATPase activity of Hsc70 to drive clathrin uncoating during clathrin-mediated endocytosis (CME) at the presynaptic terminal [PMID:22563501]. Loss-of-function mutations cause abnormal retention of assembled clathrin on synaptic vesicles and empty cages, impairing synaptic vesicle recycling, while non-neuronal cells are spared because an alternative J-domain partner compensates [PMID:22563501]; in patients, GAK is upregulated in CSF as a candidate compensatory response to auxilin loss [PMID:32472658]. Auxilin function is integrated with presynaptic phosphoinositide metabolism, as overexpression of the phosphoinositide phosphatase Synaptojanin-1 rescues the membrane phosphatidylinositol lipid alterations, neuronal dysfunction, and neurodegeneration caused by auxilin loss [PMID:36739293]. Beyond endocytosis, auxilin deficiency reduces cytosolic clathrin heavy chain and lysosomal number, downregulating lysosomal cathepsin D and impairing macroautophagy, which drives accumulation of pathologic (phospho-Ser129) α-synuclein in the ER and mitochondria, ER stress, mitochondrial depolarization, and apoptotic and neuroinflammatory (NLRP3, RIPK1-RIPK3-MLKL) death cascades in dopaminergic neurons — a cathepsin D axis confirmed causal by rapamycin rescue in a knock-in mouse [PMID:38928416, PMID:41820376]. Biallelic DNAJC6 loss-of-function mutations cause early-onset (PARK19) Parkinson's disease, with reduced auxilin protein and disrupted dopamine homeostasis in patients [PMID:26528954, PMID:32472658]. DNAJC6 expression in the substantia nigra is controlled transcriptionally by the midbrain factors NURR1 and FOXA2 and its protein stability by LRRK2, and endocytic defects from auxilin loss impair WNT-LMX1A signaling required for midbrain dopamine neuron development [PMID:33597231, PMID:41955024].","teleology":[{"year":2012,"claim":"Established that DNAJC6 encodes auxilin and that its loss disrupts Hsc70-mediated clathrin uncoating specifically in neurons, defining the core molecular defect in CME.","evidence":"Homozygosity mapping, exome sequencing and transferrin uptake assays in patient fibroblasts, with cited auxilin-null mouse data","pmids":["22563501"],"confidence":"Medium","gaps":["Identity of the compensating non-neuronal J-domain partner not defined here","Did not directly link the defect to dopaminergic vulnerability"]},{"year":2016,"claim":"Confirmed loss-of-function as the pathogenic mechanism by showing biallelic mutations collapse steady-state auxilin protein in early-onset Parkinson's disease.","evidence":"Western blot of patient fibroblasts with cosegregation and exome sequencing across two families","pmids":["26528954"],"confidence":"Medium","gaps":["Did not establish the downstream neuronal consequences of reduced protein","No mechanism linking protein loss to dopamine system"]},{"year":2020,"claim":"Linked auxilin loss to disrupted dopamine homeostasis in patients and identified GAK CSF upregulation as a candidate compensatory response.","evidence":"CSF neurotransmitter analysis, auxilin/GAK Western blots of fibroblasts and CSF, and DaTScan imaging in a patient cohort","pmids":["32472658"],"confidence":"Medium","gaps":["GAK compensation inferred from correlation, not direct functional test in human neurons","Mechanism connecting CME defect to dopamine reduction not resolved"]},{"year":2021,"claim":"Connected auxilin endocytic defects to a developmental axis, showing impaired WNT-LMX1A signaling generates vulnerable dopamine neurons with α-synuclein aggregation and organelle dysfunction.","evidence":"CRISPR-edited human ESC-derived midbrain organoids with transcriptomics and WNT-LMX1A pathway validation","pmids":["33597231"],"confidence":"Medium","gaps":["Mechanistic step from CME defect to WNT-LMX1A attenuation not fully traced","Organoid model may not capture mature adult-onset pathology"]},{"year":2023,"claim":"Defined a functional relationship between auxilin and Synaptojanin-1 through phosphoinositide metabolism, placing auxilin loss within presynaptic lipid homeostasis.","evidence":"Drosophila knock-in model with lipidomics and genetic rescue by Synaptojanin-1 overexpression","pmids":["36739293"],"confidence":"High","gaps":["Whether auxilin and SYNJ1 physically interact not established","Rescue mechanism could be parallel rather than direct epistasis"]},{"year":2024,"claim":"Directly confirmed auxilin is required for presynaptic CME and synaptic vesicle recycling in human patient neurons via gene-transfer rescue, and tied loss to midbrain patterning and maturation defects.","evidence":"Patient iPSC-derived midbrain dopaminergic neurons with isogenic controls and lentiviral DNAJC6 rescue of CME assays","pmids":["38242634"],"confidence":"High","gaps":["Did not dissect the lysosomal/autophagy arm of pathology","Relationship between neurodevelopmental defect and later neurodegeneration unresolved"]},{"year":2024,"claim":"Mapped a lysosomal cathepsin D / α-synuclein cascade downstream of auxilin loss, showing reduced clathrin and lysosomes drive ER and mitochondrial α-synuclein pathology and dopaminergic death.","evidence":"shRNA silencing and PARK19 mutant expression in SH-SY5Y neurons with lysosome, cathepsin D, α-synuclein, ER stress and mitochondrial readouts, plus α-synuclein/cathepsin D knockdown rescue","pmids":["38928416"],"confidence":"Medium","gaps":["Performed in a transformed cell line rather than authentic dopaminergic neurons","Single lab without in vivo confirmation at this stage"]},{"year":2026,"claim":"Validated the lysosomal-cathepsin D axis in vivo and extended pathology to microglial inflammasome and necroptotic death cascades, with rapamycin rescue establishing causality.","evidence":"PARK19 knock-in mouse (Dnajc6Q787X/Q787X) with rapamycin pharmacological rescue and immunohistochemical/biochemical mechanistic readouts in substantia nigra","pmids":["41820376"],"confidence":"High","gaps":["Order of events between neuronal and microglial pathology not fully resolved","Whether rapamycin benefit generalizes beyond cathepsin D restoration unclear"]},{"year":2026,"claim":"Identified upstream regulation of DNAJC6 by NURR1/FOXA2 (transcription) and LRRK2 (protein stability), and demonstrated that epigenetic restoration in neurons and astrocytes is therapeutically protective.","evidence":"Postmortem tissue, hPSC-derived midbrain cultures, transcriptional and LRRK2 stability assays, astrocyte functional assays, and CRISPRa-AAV9 in vivo gene activation in an α-synuclein PD model","pmids":["41955024"],"confidence":"Medium","gaps":["Direct molecular mechanism of LRRK2-mediated stability control not detailed","NURR1/FOXA2 regulatory claims partly rely on abstract-level reporting"]},{"year":null,"claim":"The structural basis of auxilin-Hsc70-clathrin uncoating and the precise step linking presynaptic CME failure to selective dopaminergic lysosomal/α-synuclein pathology remain to be defined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the auxilin co-chaperone cycle in the corpus","Causal chain from clathrin retention to cathepsin D loss not mechanistically resolved","Identity of compensating non-neuronal J-domain partner unconfirmed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,3]}],"complexes":[],"partners":["HSPA8","CLTC","SYNJ1","GAK","LRRK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75061","full_name":"Auxilin","aliases":["DnaJ homolog subfamily C member 6"],"length_aa":913,"mass_kda":100.0,"function":"May act as a protein phosphatase and/or a lipid phosphatase. Co-chaperone that recruits HSPA8/HSC70 to clathrin-coated vesicles (CCVs) and promotes the ATP-dependent dissociation of clathrin from CCVs and participates in clathrin-mediated endocytosis of synaptic vesicles and their recycling and also in intracellular trafficking (PubMed:18489706). Firstly, binds tightly to the clathrin cages, at a ratio of one DNAJC6 per clathrin triskelion. The HSPA8:ATP complex then binds to the clathrin-auxilin cage, initially at a ratio of one HSPA8 per triskelion leading to ATP hydrolysis stimulation and causing a conformational change in the HSPA8. This cycle is repeated three times to drive to a complex containing the clathrin-auxilin cage associated to three HSPA8:ADP complex. The ATP hydrolysis of the third HSPA8:ATP complex leads to a concerted dismantling of the cage into component triskelia. Then, dissociates from the released triskelia and be recycled to initiate another cycle of HSPA8's recruitment. Also acts during the early steps of clathrin-coated vesicle (CCV) formation through its interaction with the GTP bound form of DNM1 (By similarity)","subcellular_location":"Cytoplasmic vesicle, clathrin-coated vesicle","url":"https://www.uniprot.org/uniprotkb/O75061/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DNAJC6","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CLTA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DNAJC6","total_profiled":1310},"omim":[{"mim_id":"615528","title":"PARKINSON DISEASE 19A, JUVENILE-ONSET; PARK19A","url":"https://www.omim.org/entry/615528"},{"mim_id":"614722","title":"MICRO RNA 3120; MIR3120","url":"https://www.omim.org/entry/614722"},{"mim_id":"613735","title":"BRAIN MALFORMATIONS WITH OR WITHOUT URINARY TRACT DEFECTS; BRMUTD","url":"https://www.omim.org/entry/613735"},{"mim_id":"608375","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 6; DNAJC6","url":"https://www.omim.org/entry/608375"},{"mim_id":"604297","title":"SYNAPTOJANIN 1; SYNJ1","url":"https://www.omim.org/entry/604297"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":90.0},{"tissue":"retina","ntpm":48.9}],"url":"https://www.proteinatlas.org/search/DNAJC6"},"hgnc":{"alias_symbol":["KIAA0473","PARK19"],"prev_symbol":[]},"alphafold":{"accession":"O75061","domains":[{"cath_id":"3.90.190.10","chopping":"50-225_396-410","consensus_level":"high","plddt":83.9127,"start":50,"end":410},{"cath_id":"2.60.40.1110","chopping":"232-373","consensus_level":"high","plddt":95.0902,"start":232,"end":373},{"cath_id":"1.10.287.110","chopping":"811-908","consensus_level":"high","plddt":80.6451,"start":811,"end":908}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75061","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75061-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75061-F1-predicted_aligned_error_v6.png","plddt_mean":62.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DNAJC6","jax_strain_url":"https://www.jax.org/strain/search?query=DNAJC6"},"sequence":{"accession":"O75061","fasta_url":"https://rest.uniprot.org/uniprotkb/O75061.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75061/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75061"}},"corpus_meta":[{"pmid":"22563501","id":"PMC_22563501","title":"A deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin-uncoating co-chaperone auxilin, is associated with juvenile parkinsonism.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22563501","citation_count":240,"is_preprint":false},{"pmid":"26528954","id":"PMC_26528954","title":"DNAJC6 Mutations Associated With Early-Onset Parkinson's Disease.","date":"2016","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/26528954","citation_count":152,"is_preprint":false},{"pmid":"23211418","id":"PMC_23211418","title":"DNAJC6 is responsible for juvenile parkinsonism with phenotypic variability.","date":"2012","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/23211418","citation_count":142,"is_preprint":false},{"pmid":"33597231","id":"PMC_33597231","title":"Neurodevelopmental defects and neurodegenerative phenotypes in human brain organoids carrying Parkinson's disease-linked DNAJC6 mutations.","date":"2021","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/33597231","citation_count":117,"is_preprint":false},{"pmid":"22647716","id":"PMC_22647716","title":"Homozygous deletion of an 80 kb region comprising part of DNAJC6 and LEPR genes on chromosome 1P31.3 is associated with early onset obesity, mental retardation and epilepsy.","date":"2012","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/22647716","citation_count":38,"is_preprint":false},{"pmid":"32472658","id":"PMC_32472658","title":"DNAJC6 Mutations Disrupt Dopamine Homeostasis in Juvenile Parkinsonism-Dystonia.","date":"2020","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/32472658","citation_count":33,"is_preprint":false},{"pmid":"25446072","id":"PMC_25446072","title":"DNAJC6 promotes hepatocellular carcinoma progression through induction of epithelial-mesenchymal 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mutations.","date":"2023","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/38219303","citation_count":0,"is_preprint":false},{"pmid":"39771044","id":"PMC_39771044","title":"Risk Factors Related to Resting Metabolic Rate-Related DNAJC6 Gene Variation in Children with Overweight/Obesity: 3-Year Panel Study.","date":"2024","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/39771044","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13283,"output_tokens":3079,"usd":0.043017,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10552,"output_tokens":3685,"usd":0.072443,"stage2_stop_reason":"end_turn"},"total_usd":0.11546,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"DNAJC6 encodes the neuronal HSP40 co-chaperone auxilin, which confers specificity to the ATPase activity of Hsc70 in clathrin uncoating. Loss-of-function mutations in DNAJC6 cause abnormal retention of assembled clathrin on synaptic vesicles and in empty cages, leading to impaired synaptic vesicle recycling and perturbed clathrin-mediated endocytosis in neurons. Non-neuronal cells are unaffected because a different J-domain-containing partner compensates for auxilin in co-chaperoning Hsc70-mediated uncoating activity.\",\n      \"method\": \"Homozygosity mapping, whole exome sequencing, transferrin uptake endocytosis assay in patient fibroblasts, mRNA level analysis; prior auxilin null mouse data cited\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional endocytosis assay in patient cells plus cited null-mouse model; single lab but two orthogonal methods\",\n      \"pmids\": [\"22563501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Homozygous DNAJC6 mutations cause severely decreased steady-state levels of the auxilin protein in patient fibroblasts, confirming loss-of-function as the pathogenic mechanism in early-onset Parkinson's disease.\",\n      \"method\": \"Protein studies (Western blot) in patient-derived fibroblasts, cosegregation analysis, whole-exome sequencing\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein quantification in patient fibroblasts, replicated across two independent families\",\n      \"pmids\": [\"26528954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DNAJC6/auxilin deficiency in patients results in disrupted dopamine homeostasis, evidenced by isolated reduction of homovanillic acid in CSF, reduced presynaptic dopaminergic proteins, and significantly reduced auxilin levels in both fibroblasts and CSF. Cyclin G-associated kinase (GAK) levels in CSF were significantly increased, suggesting a compensatory upregulation of GAK upon auxilin loss, consistent with observations in the auxilin knockout mouse.\",\n      \"method\": \"CSF neurotransmitter analysis, Western blot of patient fibroblasts and CSF for auxilin and GAK, DaTScan (123I-FP-CIT SPECT), whole-exome sequencing\",\n      \"journal\": \"Movement disorders : official journal of the Movement Disorder Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (biochemical CSF analysis, protein quantification, neuroimaging) in patient cohort, single lab\",\n      \"pmids\": [\"32472658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DNAJC6 mutations in human midbrain-like organoids cause degeneration of midbrain-type dopamine neurons, pathologic α-synuclein aggregation, increased intrinsic neuronal firing frequency, and mitochondrial and lysosomal dysfunctions. Mechanistically, DNAJC6-mediated endocytosis defects impair the WNT-LMX1A signaling pathway during midbrain dopamine neuron development, and reduced LMX1A expression generates vulnerable neurons with pathologic manifestations.\",\n      \"method\": \"CRISPR-Cas9 gene editing of human embryonic stem cells, human midbrain-like organoids (hMLOs), transcriptomic analyses, experimental validation of WNT-LMX1A signaling pathway\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR loss-of-function with multiple orthogonal readouts and pathway validation in human organoid model, single lab\",\n      \"pmids\": [\"33597231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In a Drosophila knock-in model of DNAJC6/Auxilin pathogenic mutation, loss of auxilin causes synaptic dysfunction, neurological defects, neurodegeneration, and specific lipid metabolism alterations including reduction of membrane phosphatidylinositol lipid species containing long-chain polyunsaturated fatty acids. Overexpression of Synaptojanin-1 (SYNJ1), which binds and metabolizes phosphoinositides, rescues the DNAJC6/Auxilin lipid alterations, neuronal function defects, and neurodegeneration, establishing a functional relationship between auxilin and SYNJ1 through phosphoinositide metabolism.\",\n      \"method\": \"Drosophila knock-in model, lipidomics, genetic rescue by Synaptojanin-1 overexpression, neurological/behavioral assays, neurodegeneration readouts\",\n      \"journal\": \"NPJ Parkinson's disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo knock-in model with lipidomics plus genetic epistasis rescue, multiple orthogonal methods establishing pathway relationship\",\n      \"pmids\": [\"36739293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In iPSC-derived midbrain dopaminergic neurons from DNAJC6 loss-of-function patients, auxilin deficiency disturbs synaptic vesicle recycling and homeostasis, and causes neurodevelopmental dysregulation affecting ventral midbrain patterning and neuronal maturation. Lentiviral DNAJC6 gene transfer restored auxilin expression and rescued clathrin-mediated endocytosis, directly confirming that auxilin is required for CME at the presynaptic terminal.\",\n      \"method\": \"iPSC generation from patients, CRISPR-corrected isogenic controls, lentiviral gene transfer rescue, functional CME assays, synaptic vesicle recycling assays\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — gene transfer rescue with functional CME assay in isogenic-controlled patient-derived neurons, multiple orthogonal methods\",\n      \"pmids\": [\"38242634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DNAJC6 paucity in differentiated human SH-SY5Y dopaminergic neurons reduces cytosolic clathrin heavy chain levels and lysosomal number, which downregulates lysosomal cathepsin D and impairs macroautophagy, leading to upregulation of pathologic α-synuclein (including phospho-α-synuclein Ser129) in the ER and mitochondria. ER α-synuclein accumulation activates ER stress, the unfolded protein response, and apoptotic signaling; mitochondrial α-synuclein depolarizes mitochondrial membrane potential and increases superoxide. Knockdown of α-synuclein or cathepsin D blocked DNAJC6 deficiency-evoked dopaminergic cell degeneration. PARK19 DNAJC6 mutants (Q789X or R927G) failed to attenuate tunicamycin- or rotenone-induced upregulation of pathologic α-synuclein and apoptotic signaling, unlike WT DNAJC6.\",\n      \"method\": \"shRNA-mediated gene silencing in differentiated SH-SY5Y neurons, lysosome quantification, cathepsin D assay, α-synuclein immunofluorescence, mitochondrial membrane potential measurement, superoxide assay, ER stress markers, mutant protein rescue experiments\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in cell model with both KD and mutant expression, single lab\",\n      \"pmids\": [\"38928416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In a PARK19 knock-in mouse model (Dnajc6Q787X/Q787X), truncated Dnajc6 decreases clathrin heavy chain and lysosomal number in substantia nigra dopaminergic neurons, leading to downregulation of lysosomal cathepsin D and upregulation of α-synuclein and α-synuclein oligomers, ER stress, mitochondrial apoptotic cascades, microglial NLRP3 inflammasome activation, and neuroinflammatory cell death cascades (RIPK1-RIPK3-MLKL). Rapamycin (lysosomal biogenesis activator) precluded cathepsin D downregulation, α-synuclein upregulation, and PARK19 phenotypes, confirming the causal lysosomal-cathepsin D axis.\",\n      \"method\": \"PARK19 knock-in mouse model, rapamycin pharmacological rescue, immunohistochemistry, lysosome/cathepsin D quantification, α-synuclein/oligomer detection, NLRP3 inflammasome markers, death cascade protein analysis\",\n      \"journal\": \"NPJ Parkinson's disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo knock-in mouse model with pharmacological rescue and multiple orthogonal mechanistic readouts\",\n      \"pmids\": [\"41820376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DNAJC6 expression in the substantia nigra is regulated transcriptionally by the midbrain-specific factors NURR1 and FOXA2, and protein stability is regulated by LRRK2. In astrocytes, DNAJC6 deficiency impairs phagocytic, autolysosomal, and mitochondrial functions while promoting a proinflammatory phenotype. CRISPRa-AAV9-mediated epigenetic restoration of DNAJC6 in neurons and astrocytes in an α-synuclein-induced mouse PD model alleviated behavioral deficits and neuropathology.\",\n      \"method\": \"Postmortem tissue analysis, hPSC-derived midbrain cultures, mechanistic studies of NURR1/FOXA2 transcriptional regulation, LRRK2-mediated protein stability assays, astrocyte functional assays (phagocytosis, autolysosomal, mitochondrial), CRISPRa-AAV9 in vivo gene activation\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including in vivo rescue; mechanistic claims about NURR1/FOXA2 and LRRK2 from single lab, some aspects rely on abstract-level reporting\",\n      \"pmids\": [\"41955024\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DNAJC6 encodes auxilin, a neuronal HSP40 co-chaperone that activates Hsc70 ATPase activity to drive clathrin uncoating during clathrin-mediated endocytosis (CME) at the presynaptic terminal; loss of auxilin impairs synaptic vesicle recycling, reduces clathrin heavy chain and lysosomal number, disrupts phosphoinositide and lipid homeostasis (functionally linked to Synaptojanin-1), downregulates lysosomal cathepsin D, and causes pathologic α-synuclein accumulation with ER stress, mitochondrial dysfunction, and neuroinflammatory cell death cascades leading to dopaminergic neuron degeneration; auxilin transcription is controlled by NURR1/FOXA2 and its protein stability is regulated by LRRK2, while GAK compensates for auxilin loss in non-neuronal cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DNAJC6 encodes auxilin, a neuronal HSP40 co-chaperone that confers substrate specificity to the ATPase activity of Hsc70 to drive clathrin uncoating during clathrin-mediated endocytosis (CME) at the presynaptic terminal [#0]. Loss-of-function mutations cause abnormal retention of assembled clathrin on synaptic vesicles and empty cages, impairing synaptic vesicle recycling, while non-neuronal cells are spared because an alternative J-domain partner compensates [#0]; in patients, GAK is upregulated in CSF as a candidate compensatory response to auxilin loss [#2]. Auxilin function is integrated with presynaptic phosphoinositide metabolism, as overexpression of the phosphoinositide phosphatase Synaptojanin-1 rescues the membrane phosphatidylinositol lipid alterations, neuronal dysfunction, and neurodegeneration caused by auxilin loss [#4]. Beyond endocytosis, auxilin deficiency reduces cytosolic clathrin heavy chain and lysosomal number, downregulating lysosomal cathepsin D and impairing macroautophagy, which drives accumulation of pathologic (phospho-Ser129) \\u03b1-synuclein in the ER and mitochondria, ER stress, mitochondrial depolarization, and apoptotic and neuroinflammatory (NLRP3, RIPK1-RIPK3-MLKL) death cascades in dopaminergic neurons \\u2014 a cathepsin D axis confirmed causal by rapamycin rescue in a knock-in mouse [#6, #7]. Biallelic DNAJC6 loss-of-function mutations cause early-onset (PARK19) Parkinson's disease, with reduced auxilin protein and disrupted dopamine homeostasis in patients [#1, #2]. DNAJC6 expression in the substantia nigra is controlled transcriptionally by the midbrain factors NURR1 and FOXA2 and its protein stability by LRRK2, and endocytic defects from auxilin loss impair WNT-LMX1A signaling required for midbrain dopamine neuron development [#3, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that DNAJC6 encodes auxilin and that its loss disrupts Hsc70-mediated clathrin uncoating specifically in neurons, defining the core molecular defect in CME.\",\n      \"evidence\": \"Homozygosity mapping, exome sequencing and transferrin uptake assays in patient fibroblasts, with cited auxilin-null mouse data\",\n      \"pmids\": [\"22563501\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Identity of the compensating non-neuronal J-domain partner not defined here\", \"Did not directly link the defect to dopaminergic vulnerability\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Confirmed loss-of-function as the pathogenic mechanism by showing biallelic mutations collapse steady-state auxilin protein in early-onset Parkinson's disease.\",\n      \"evidence\": \"Western blot of patient fibroblasts with cosegregation and exome sequencing across two families\",\n      \"pmids\": [\"26528954\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not establish the downstream neuronal consequences of reduced protein\", \"No mechanism linking protein loss to dopamine system\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked auxilin loss to disrupted dopamine homeostasis in patients and identified GAK CSF upregulation as a candidate compensatory response.\",\n      \"evidence\": \"CSF neurotransmitter analysis, auxilin/GAK Western blots of fibroblasts and CSF, and DaTScan imaging in a patient cohort\",\n      \"pmids\": [\"32472658\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"GAK compensation inferred from correlation, not direct functional test in human neurons\", \"Mechanism connecting CME defect to dopamine reduction not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected auxilin endocytic defects to a developmental axis, showing impaired WNT-LMX1A signaling generates vulnerable dopamine neurons with \\u03b1-synuclein aggregation and organelle dysfunction.\",\n      \"evidence\": \"CRISPR-edited human ESC-derived midbrain organoids with transcriptomics and WNT-LMX1A pathway validation\",\n      \"pmids\": [\"33597231\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanistic step from CME defect to WNT-LMX1A attenuation not fully traced\", \"Organoid model may not capture mature adult-onset pathology\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a functional relationship between auxilin and Synaptojanin-1 through phosphoinositide metabolism, placing auxilin loss within presynaptic lipid homeostasis.\",\n      \"evidence\": \"Drosophila knock-in model with lipidomics and genetic rescue by Synaptojanin-1 overexpression\",\n      \"pmids\": [\"36739293\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether auxilin and SYNJ1 physically interact not established\", \"Rescue mechanism could be parallel rather than direct epistasis\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Directly confirmed auxilin is required for presynaptic CME and synaptic vesicle recycling in human patient neurons via gene-transfer rescue, and tied loss to midbrain patterning and maturation defects.\",\n      \"evidence\": \"Patient iPSC-derived midbrain dopaminergic neurons with isogenic controls and lentiviral DNAJC6 rescue of CME assays\",\n      \"pmids\": [\"38242634\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not dissect the lysosomal/autophagy arm of pathology\", \"Relationship between neurodevelopmental defect and later neurodegeneration unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped a lysosomal cathepsin D / \\u03b1-synuclein cascade downstream of auxilin loss, showing reduced clathrin and lysosomes drive ER and mitochondrial \\u03b1-synuclein pathology and dopaminergic death.\",\n      \"evidence\": \"shRNA silencing and PARK19 mutant expression in SH-SY5Y neurons with lysosome, cathepsin D, \\u03b1-synuclein, ER stress and mitochondrial readouts, plus \\u03b1-synuclein/cathepsin D knockdown rescue\",\n      \"pmids\": [\"38928416\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Performed in a transformed cell line rather than authentic dopaminergic neurons\", \"Single lab without in vivo confirmation at this stage\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Validated the lysosomal-cathepsin D axis in vivo and extended pathology to microglial inflammasome and necroptotic death cascades, with rapamycin rescue establishing causality.\",\n      \"evidence\": \"PARK19 knock-in mouse (Dnajc6Q787X/Q787X) with rapamycin pharmacological rescue and immunohistochemical/biochemical mechanistic readouts in substantia nigra\",\n      \"pmids\": [\"41820376\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Order of events between neuronal and microglial pathology not fully resolved\", \"Whether rapamycin benefit generalizes beyond cathepsin D restoration unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified upstream regulation of DNAJC6 by NURR1/FOXA2 (transcription) and LRRK2 (protein stability), and demonstrated that epigenetic restoration in neurons and astrocytes is therapeutically protective.\",\n      \"evidence\": \"Postmortem tissue, hPSC-derived midbrain cultures, transcriptional and LRRK2 stability assays, astrocyte functional assays, and CRISPRa-AAV9 in vivo gene activation in an \\u03b1-synuclein PD model\",\n      \"pmids\": [\"41955024\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct molecular mechanism of LRRK2-mediated stability control not detailed\", \"NURR1/FOXA2 regulatory claims partly rely on abstract-level reporting\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of auxilin-Hsc70-clathrin uncoating and the precise step linking presynaptic CME failure to selective dopaminergic lysosomal/\\u03b1-synuclein pathology remain to be defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of the auxilin co-chaperone cycle in the corpus\", \"Causal chain from clathrin retention to cathepsin D loss not mechanistically resolved\", \"Identity of compensating non-neuronal J-domain partner unconfirmed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HSPA8\", \"CLTC\", \"SYNJ1\", \"GAK\", \"LRRK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}