Objective: To investigate whether DDX17, an RNA helicase identified as a Parkinson’s disease (PD) risk gene, regulates astrocytic mitochondrial metabolism and contributes to dopaminergic neuron degeneration.
Background: Mitochondrial dysfunction in astrocytes is implicated in PD pathogenesis, but upstream regulators remain unknown. Integrating Mendelian randomization and single-cell transcriptomics, we identified DDX17 as a PD risk gene specifically upregulated in astrocytes. Its genetic variant rs2267390 correlates with higher expression and faster disease progression. RIP-seq and IP-MS revealed DDX17 binds mRNAs encoding TCA cycle and electron transport chain enzymes, suggesting a role in oxidative phosphorylation (OXPHOS) regulation.
Method: We utilized primary astrocytes, SVG p12 cells, and MPTP/rotenone-induced PD models. RNA stability, mitochondrial respiration (Seahorse), ROS production, mitophagy flux, and neuronal survival were assessed. Truncation mutants mapped functional domains. A dual-targeting nanocarrier (Angiopep-2/aMTD/lipo) was developed for brain and mitochondrial delivery of a DDX17 inhibitor.
Results: DDX17 was significantly elevated in PD patient astrocytes and correlated with disease severity. Overexpression enhanced mitochondrial gene mRNA stability, leading to OXPHOS hyperactivation, elevated ROS, and suppressed mitophagy, resulting in astrocytic dysfunction and increased neuronal vulnerability. The pathogenic effect was mapped to a C-terminal RGG-containing domain. Pharmacological inhibition of DDX17 or OXPHOS reversed these effects and improved motor function in PD mice. The dual-targeted nanocarrier achieved efficient brain delivery and mitochondrial localization, attenuating neurodegeneration and α-synuclein pathology.
Conclusion: DDX17 is a novel upstream regulator of astrocytic mitochondrial metabolism in PD. Targeting its functional domain or downstream OXPHOS hyperactivity offers a promising disease-modifying strategy.
To cite this abstract in AMA style:
XIA. Dong, GAN. Wu, XIN. Yang, QIN. Li, FUR. Jin, RUI. Li, HON. Li, RUI. Xu. DDX17 Drives Astrocytic Mitochondrial Metabolic Reprogramming and Contributes to Parkinson’s Disease Progression [abstract]. Mov Disord. 2026; 41 (suppl 1). https://www.mdsabstracts.org/abstract/ddx17-drives-astrocytic-mitochondrial-metabolic-reprogramming-and-contributes-to-parkinsons-disease-progression/. Accessed October 1, 2026.« Back to 2026 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/ddx17-drives-astrocytic-mitochondrial-metabolic-reprogramming-and-contributes-to-parkinsons-disease-progression/