| 2012 |
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. |
Homozygosity mapping, whole exome sequencing, transferrin uptake endocytosis assay in patient fibroblasts, mRNA level analysis; prior auxilin null mouse data cited |
PloS one |
Medium |
22563501
|
| 2016 |
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. |
Protein studies (Western blot) in patient-derived fibroblasts, cosegregation analysis, whole-exome sequencing |
Annals of neurology |
Medium |
26528954
|
| 2020 |
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. |
CSF neurotransmitter analysis, Western blot of patient fibroblasts and CSF for auxilin and GAK, DaTScan (123I-FP-CIT SPECT), whole-exome sequencing |
Movement disorders : official journal of the Movement Disorder Society |
Medium |
32472658
|
| 2021 |
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. |
CRISPR-Cas9 gene editing of human embryonic stem cells, human midbrain-like organoids (hMLOs), transcriptomic analyses, experimental validation of WNT-LMX1A signaling pathway |
Science advances |
Medium |
33597231
|
| 2023 |
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. |
Drosophila knock-in model, lipidomics, genetic rescue by Synaptojanin-1 overexpression, neurological/behavioral assays, neurodegeneration readouts |
NPJ Parkinson's disease |
High |
36739293
|
| 2024 |
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. |
iPSC generation from patients, CRISPR-corrected isogenic controls, lentiviral gene transfer rescue, functional CME assays, synaptic vesicle recycling assays |
Brain : a journal of neurology |
High |
38242634
|
| 2024 |
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. |
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 |
International journal of molecular sciences |
Medium |
38928416
|
| 2026 |
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. |
PARK19 knock-in mouse model, rapamycin pharmacological rescue, immunohistochemistry, lysosome/cathepsin D quantification, α-synuclein/oligomer detection, NLRP3 inflammasome markers, death cascade protein analysis |
NPJ Parkinson's disease |
High |
41820376
|
| 2026 |
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. |
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 |
The Journal of clinical investigation |
Medium |
41955024
|