| Pathway/Process | Auxilin's Specific Role | Key Interacting Proteins | Functional Consequences of Deficiency |
|---|---|---|---|
| Clathrin-mediated endocytosis (CME) | Auxilin/DNAJC6 acts at the terminal uncoating step of CME by binding clathrin-coated vesicles and recruiting HSC70 through its J-domain to stimulate HSC70 ATPase activity and disassemble the clathrin coat; membrane recruitment is coordinated with phosphoinositide state during vesicle maturation (pqac-00000001, pqac-00000003, pqac-00000006) | HSC70/HSPA8, clathrin heavy chain, AP-2/adaptor machinery, dynamin, synaptojanin-1 (pqac-00000003, pqac-00000006, pqac-00000007) | Accumulation of clathrin-coated vesicles and empty clathrin cages, slower or failed uncoating, impaired endocytic membrane trafficking, and reduced cytosolic clathrin homeostasis in dopaminergic neurons (pqac-00000001, pqac-00000005, pqac-00000007) |
| Synaptic vesicle recycling | At presynaptic peri-active zones, auxilin regenerates synaptic vesicles from newly formed coated vesicles, helping maintain vesicle availability for repeated neurotransmission and preserving the readily releasable/recycling pools (pqac-00000001, pqac-00000004, pqac-00000005) | HSC70, clathrin, dynamin, synaptojanin-1, endophilin-associated endocytic machinery (pqac-00000004, pqac-00000005, pqac-00000006) | Disturbed synaptic vesicle recycling and homeostasis, depletion or abnormal refilling of releasable vesicle pools, impaired presynaptic short-term plasticity, altered visual/circuit responses, and synaptic dysfunction preceding neurodegeneration (pqac-00000001, pqac-00000005, pqac-00000006) |
| Endolysosomal pathway | Recent work places DNAJC6 beyond synaptic uncoating, linking it to endolysosomal maintenance and vesicular trafficking in neurons and glia; auxilin dysfunction appears to compromise lysosome-associated trafficking and degradative capacity (pqac-00000008, pqac-00000010) | LRRK2-regulated pathways, α-synuclein-linked vesicular networks, lysosomal proteases including cathepsin D (pqac-00000007, pqac-00000008, pqac-00000010) | Reduced lysosome number, defective endolysosomal clearance, buildup of toxic proteins/organelles, enhanced neuronal stress, and contribution to dopaminergic degeneration and sporadic PD-associated pathology (pqac-00000007, pqac-00000008, pqac-00000010) |
| Phosphoinositide metabolism | Auxilin function is coordinated with phosphoinositide remodeling during endocytosis; after synaptojanin-1 dephosphorylates PI(4,5)P2, auxilin/HSC70 recruitment promotes coat removal. Auxilin also contains a PTEN-like phosphoinositide-binding region that likely helps target it to vesicle membranes (pqac-00000000, pqac-00000006) | Synaptojanin-1/SYNJ1, PI(4,5)P2, clathrin adaptors, HSC70 (pqac-00000000, pqac-00000006) | Failure to couple lipid remodeling to coat removal, persistence of endocytic intermediates, defective vesicle recycling, and strong functional synergy with SYNJ1-related Parkinsonism pathways (pqac-00000000, pqac-00000002, pqac-00000006) |
| Lipid homeostasis | Pathogenic DNAJC6 mutations alter neuronal membrane lipid composition, especially long-chain polyunsaturated fatty acid-containing lipids and phosphatidylinositol species important for synaptic vesicle recycling and organelle function (pqac-00000000) | Synaptojanin-1, phosphatidylinositol lipid species, long-chain PUFA-containing membrane lipids (pqac-00000000) | Lipid imbalance, synaptic dysfunction, neurological defects, and neurodegeneration; in Drosophila, Synj1 overexpression rescues lipid defects and neuronal phenotypes, supporting functional coupling between auxilin and phosphoinositide/lipid metabolism (pqac-00000000) |
| Autophagy / autolysosomal clearance | Auxilin deficiency has emerging downstream effects on autophagy, likely secondary to disrupted vesicle trafficking and lysosomal homeostasis; recent studies link DNAJC6 loss to impaired autolysosomal and macroautophagic function in neurons and astrocytes (pqac-00000002, pqac-00000007, pqac-00000008) | Cathepsin D, α-synuclein, lysosomes, LRRK2-associated regulatory pathways (pqac-00000007, pqac-00000008) | Impaired macroautophagy, accumulation of pathologic α-synuclein/phospho-α-synuclein, ER stress, mitochondrial dysfunction, inflammatory astrocyte phenotypes, and enhanced neurodegeneration (pqac-00000007, pqac-00000008) |


*Table: This table summarizes the principal cellular pathways involving DNAJC6/auxilin and highlights its mechanistic roles, interacting proteins, and the functional consequences of loss or mutation. It is useful for functional annotation because it connects the protein's core synaptic uncoating function to broader endolysosomal, lipid, and autophagic phenotypes reported in recent literature.*