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ResearchIn-Press PreviewClinical ResearchNeuroscience Open Access | 10.1172/JCI194989

Dysregulation of astrocytic DNAJC6 contributes to sporadic Parkinson’s disease pathogenesis

Wahyu Handoko Wibowo Darsono,1 Yeongran Hwang,1 Erica Valencia,1 Leonardo Tejo Gunawan,1 Seung Jae Hyeon,2 Hoon Ryu,2 Thor D. Stein,3 Mi-Yoon Chang,4 Noviana Wulansari,1 and Sang-Hun Lee1

1Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea, Republic of

2Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea, Republic of

3Boston University Alzheimer’s Disease Center and Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, United States of America

4Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea, Republic of

5Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea, Democratic Peoples Republic of

Find articles by Darsono, W. in: PubMed | Google Scholar

1Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea, Republic of

2Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea, Republic of

3Boston University Alzheimer’s Disease Center and Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, United States of America

4Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea, Republic of

5Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea, Democratic Peoples Republic of

Find articles by Hwang, Y. in: PubMed | Google Scholar

1Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea, Republic of

2Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea, Republic of

3Boston University Alzheimer’s Disease Center and Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, United States of America

4Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea, Republic of

5Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea, Democratic Peoples Republic of

Find articles by Valencia, E. in: PubMed | Google Scholar

1Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea, Republic of

2Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea, Republic of

3Boston University Alzheimer’s Disease Center and Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, United States of America

4Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea, Republic of

5Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea, Democratic Peoples Republic of

Find articles by Gunawan, L. in: PubMed | Google Scholar

1Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea, Republic of

2Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea, Republic of

3Boston University Alzheimer’s Disease Center and Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, United States of America

4Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea, Republic of

5Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea, Democratic Peoples Republic of

Find articles by Hyeon, S. in: PubMed | Google Scholar

1Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea, Republic of

2Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea, Republic of

3Boston University Alzheimer’s Disease Center and Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, United States of America

4Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea, Republic of

5Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea, Democratic Peoples Republic of

Find articles by Ryu, H. in: PubMed | Google Scholar

1Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea, Republic of

2Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea, Republic of

3Boston University Alzheimer’s Disease Center and Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, United States of America

4Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea, Republic of

5Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea, Democratic Peoples Republic of

Find articles by Stein, T. in: PubMed | Google Scholar

1Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea, Republic of

2Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea, Republic of

3Boston University Alzheimer’s Disease Center and Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, United States of America

4Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea, Republic of

5Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea, Democratic Peoples Republic of

Find articles by Chang, M. in: PubMed | Google Scholar

1Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea, Republic of

2Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea, Republic of

3Boston University Alzheimer’s Disease Center and Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, United States of America

4Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea, Republic of

5Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea, Democratic Peoples Republic of

Find articles by Wulansari, N. in: PubMed | Google Scholar

1Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea, Republic of

2Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea, Republic of

3Boston University Alzheimer’s Disease Center and Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, United States of America

4Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea, Republic of

5Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea, Democratic Peoples Republic of

Find articles by Lee, S. in: PubMed | Google Scholar

Published April 9, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI194989.
Copyright © 2026, Darsono et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 9, 2026 - Version history
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Abstract

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.

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  • Version 1 (April 9, 2026): In-Press Preview
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