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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\u2013derived midbrain cultures exhibited reduced DNAJC6 expression under multiple PD-associated conditions. Mechanistically, DNAJC6 loss resulted from impaired transcription mediated by the 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 proinflammatory 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 \u03b1-synuclein\u2013induced 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.<\/jats:p>","DOI":"10.1172\/jci194989","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T16:00:15Z","timestamp":1775750415000},"source":"Crossref","is-referenced-by-count":0,"title":["Dysregulation of astrocytic DNAJC6 contributes to sporadic Parkinson\u2019s disease pathogenesis"],"prefix":"10.1172","volume":"136","author":[{"given":"Wahyu Handoko Wibowo","family":"Darsono","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, College of Medicine,"},{"name":"Hanyang Biomedical Research Institute, and"},{"name":"Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South 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