The paper shows DNAJC6 is downregulated in neurons and astrocytes in sporadic PD, links that loss to impaired autolysosomal, mitochondrial, phagocytic function and pro-inflammatory astrocyte phenotypes via NURR1/FOXA2 and LRRK2-related mechanisms, and demonstrates that CRISPRa-AAV9–mediated…

Identifies DNAJC6 as a disease-modifying target that connects key PD pathways (α-synuclein, lysosomes, mitochondria, inflammation, LRRK2) and validates a translational intervention (AAV-CRISPRa) with cell-type specificity, making it highly relevant for therapeutic development and biomarker efforts.

Loss-of-function mutations in DNAJC6, encoding the co-chaperone auxilin (HSP40 family), cause familial juvenile-onset Parkinson's disease (PD). Given the chaperone role of DNAJC6 in cellular homeostasis in adult neurons, we hypothesized that DNAJC6 dysfunction may not be limited to juvenile-onset disorders but could also be associated with adult-onset brain diseases. Here, we show that DNAJC6 expression is significantly downregulated in postmortem substantia nigra tissues and transcriptomic datasets from patients with late-onset sporadic PD. Consistently, human pluripotent stem cell-derived midbrain cultures exhibited reduced DNAJC6 expression under multiple PD-associated conditions. Mechanistically, DNAJC6 loss resulted from impaired transcription mediated by midbrain-specific factors NURR1/FOXA2 and reduced protein stability regulated by LRRK2. Beyond neurons, DNAJC6 was robustly expressed in astrocytes and similarly downregulated in sporadic PD contexts. Astrocytic DNAJC6 deficiency impaired phagocytic, autolysosomal, and mitochondrial functions while promoting a pro-inflammatory phenotype, thereby exacerbating neurodegenerative pathology. Importantly, epigenetic restoration of DNAJC6 in neurons and astrocytes using a CRISPRa-AAV9 system in the substantia nigra of an α-synuclein-induced PD mouse model alleviated behavioral deficits and neuropathology. These findings provide evidence that DNAJC6 dysregulation is associated with pathogenic processes in sporadic PD and suggest that targeting neuronal and astrocytic DNAJC6 could represent a potential disease-modifying strategy.