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Neuroprotective effect of astrocytic dopamine Drd2 receptor on mitochondrial complex I in a mouse model of Parkinson’s disease through β-arrestin2-NDUFA10 regulation

Cell Death & Differentiation (2026) Cite this article

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Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disease. Current treatment strategies for PD mainly focus on dopamine replacement and regulation of dopaminergic signaling. Here, we reveal the unique role of the astrocytic dopamine D2 (Drd2) receptor in regulating mitochondrial function, thereby improving Parkinson’s disease-like symptoms in a mouse model. Transcriptome sequencing and metabolomics suggest that deletion of astrocytic Drd2 receptor significantly aggravates mitochondrial dysfunction. Mechanistically, we demonstrate that the Drd2 receptor regulates mitochondrial complex I activity by recruiting the scaffold protein β-arrestin2, which facilitates its interaction with NDUFA4 and NDUFA10, two subunits of mitochondrial complex I. Notably, the neuroprotective effect of Drd2 activation in vivo was completely abolished upon selective knockdown of NDUFA10 in mouse astrocytes. The identification of this novel mechanistic axis not only elucidates how astrocytes maintain neuronal mitochondrial homeostasis via dopaminergic signaling but also establishes a transformative framework for the development of targeted combination therapies that concurrently address mitochondrial dysfunction and dopamine receptor dysregulation as a promising avenue for advancing PD treatment strategies.

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Fig. 1: Expression of Astrocytic Dopamine D2 Receptor (Drd2) in Major Brain Regions.
The alternative text for this image may have been generated using AI.
Fig. 2: Astrocytic Drd2 Deficiency Aggravates Motor Imbalance, DA neuron loss and reactive astrogliosis in the MPTP/p mouse model.
The alternative text for this image may have been generated using AI.
Fig. 3: Astrocytic Drd2 deficiency induces mitochondrial morphological abnormalities and dysfunction.
The alternative text for this image may have been generated using AI.
Fig. 4: Drd2 receptors regulate mitochondrial function via the β-arrestin2 signaling pathway rather than the classical G protein-coupled receptor (GPCR) pathway.
The alternative text for this image may have been generated using AI.
Fig. 5: Astrocytic Drd2 deficiency disrupts the formation of β-arrestin2-NDUFA4/10 complex.
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Fig. 6: Astrocytic Drd2 sustains mitochondrial function and neuronal viability via a β-arrestin2-dependent and gαi/o protein-independent pathway.
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Fig. 7: Astrocytic NDUFA10 knockdown abolishes Drd2 pathway-mediated neuroprotection in the MPTP/p mouse model.
The alternative text for this image may have been generated using AI.
Fig. 8: The schematic illustration depicts the neuroprotective effect of the astrocytic D2 dopamine receptor (Drd2) on mitochondrial complex I activity in PD model mice via β-arrestin2-mediated regulation of NDUFA4 and NDUFA10.
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References

  1. Clayton DF, George JM. The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends Neurosci. 1998;21:249–54.

    Article  CAS  PubMed  Google Scholar 

  2. Geddes JF, Hughes AJ, Lees AJ, Daniel SE. Pathological overlap in cases of Parkinsonism associated with neurofibrillary tangles. A study of recent cases of postencephalitic Parkinsonism and comparison with progressive supranuclear palsy and Guamanian Parkinsonism-Dementia Complex. Brain. 1993;116:281–302.

    Article  PubMed  Google Scholar 

  3. Berg D, Postuma RB, Bloem B, Chan P, Dubois B, Gasser T, et al. Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson’s disease. Mov Disord. 2014;29:454–62.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Nicoletti V, Palermo G, Del Prete E, Mancuso M, Ceravolo R. Understanding the multiple role of mitochondria in Parkinson’s disease and related disorders: lesson from genetics and protein-interaction networks. Front Cell Dev Biol. 2021;9:636506.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Group PDMC, Gray R, Ives N, Rick C, Patel S, Gray A, et al. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson’s disease (PD MED): a large, open-label, pragmatic randomised trial. Lancet. 2014;384:1196–205.

    Article  Google Scholar 

  6. Kalia LV, Lang AE. Parkinson's disease in 2015: evolving basic, pathological and clinical concepts in PD. Nat Rev Neurol. 2016;12:65–6.

    Article  CAS  PubMed  Google Scholar 

  7. Jesús S, Perinan MT, Cortés C, Buiza-Rueda D, Macías-García D, Adarmes A, et al. Integrating genetic and clinical data to predict impulse control disorders in Parkinson’s disease. Eur J Neurol. 2021;28:459–68.

    Article  PubMed  Google Scholar 

  8. German CL, Baladi MG, McFadden LM, Hanson GR, Fleckenstein AE. Regulation of the dopamine and vesicular monoamine transporters: pharmacological targets and implications for disease. Pharm Rev. 2015;67:1005–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Latif S, Jahangeer M, Maknoon Razia D, Ashiq M, Ghaffar A, Akram M, et al. Dopamine in Parkinson’s disease. Clin Chim Acta. 2021;522:114–26.

    Article  CAS  PubMed  Google Scholar 

  10. Zhu C, Zhang Z, Zhu Y, Du Y, Han C, Zhao Q, et al. Study on the role of Dihuang Yinzi in regulating the AMPK/SIRT1/PGC-1alpha pathway to promote mitochondrial biogenesis and improve Alzheimer’s disease. J Ethnopharmacol. 2025;337:118859.

    Article  CAS  PubMed  Google Scholar 

  11. Eleuteri S, Wang B, Cutillo G, Zhang Fang TS, Tao K, Qu Y, et al. PGC-1alpha regulation by FBXW7 through a novel mechanism linking chaperone-mediated autophagy and the ubiquitin-proteasome system. FEBS J. 2025;292:332–54.

    Article  CAS  PubMed  Google Scholar 

  12. Zhang S, Li M, Li Y, Yang S, Wang J, Ren X, et al. Mitochondria-targeted nanovesicles for ursodeoxycholic acid delivery to combat neurodegeneration by ameliorating mitochondrial dysfunction. J Nanobiotechnology. 2025;23:202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Payne T, Appleby M, Buckley E, van Gelder LMA, Mullish BH, Sassani M, et al. A double-blind, randomized, placebo-controlled trial of ursodeoxycholic acid (UDCA) in Parkinson’s disease. Mov Disord. 2023;38:1493–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sharma K, Sarkar J, Trisal A, Ghosh R, Dixit A, Singh AK. Targeting mitochondrial dysfunction to salvage cellular senescence for managing neurodegeneration. Adv Protein Chem Struct Biol. 2023;136:309–37.

    Article  CAS  PubMed  Google Scholar 

  15. Ghosh A, Chandran K, Kalivendi SV, Joseph J, Antholine WE, Hillard CJ, et al. Neuroprotection by a mitochondria-targeted drug in a Parkinson’s disease model. Free Radic Biol Med. 2010;49:1674–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Subhramanyam CS, Wang C, Hu Q, Dheen ST. Microglia-mediated neuroinflammation in neurodegenerative diseases. Semin Cell Dev Biol. 2019;94:112–20.

    Article  CAS  PubMed  Google Scholar 

  17. Lines J, Corkrum M, Aguilar J, Araque A. The duality of astrocyte neuromodulation: astrocytes sense neuromodulators and are neuromodulators. J Neurochem. 2025;169:e70054.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wilton DK, Dissing-Olesen L, Stevens B. Neuron-glia signaling in synapse elimination. Annu Rev Neurosci. 2019;42:107–27.

    Article  CAS  PubMed  Google Scholar 

  19. Brady LJ, Bartley AF, Li Q, McMeekin LJ, Hablitz JJ, Cowell RM, et al. Transcriptional dysregulation causes altered modulation of inhibition by haloperidol. Neuropharmacology. 2016;111:304–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cassina P, Miquel E, Martinez-Palma L, Cassina A. Mitochondria and astrocyte reactivity: key mechanism behind neuronal injury. Neuroscience. 2025;567:227–34.

    Article  CAS  PubMed  Google Scholar 

  21. Zhu J, Sun T, Zhang J, Liu Y, Wang D, Zhu H, et al. Drd2 biased agonist prevents neurodegeneration against NLRP3 inflammasome in Parkinson’s disease model via a beta-arrestin2-biased mechanism. Brain Behav Immun. 2020;90:259–71.

    Article  CAS  PubMed  Google Scholar 

  22. Moo EV, van Senten JR, Brauner-Osborne H, Moller TC. Arrestin-dependent and -independent internalization of G protein-coupled receptors: methods, mechanisms, and implications on cell signaling. Mol Pharmacol. 2021;99:242–55.

    Article  CAS  PubMed  Google Scholar 

  23. Tian X, Kang DS, Benovic JL. Beta-arrestins and G protein-coupled receptor trafficking. Handb Exp Pharmacol. 2014;219:173–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ferguson SS. Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharm Rev. 2001;53:1–24.

    Article  CAS  PubMed  Google Scholar 

  25. Qi M, Chen TT, Li L, Gao PP, Li N, Zhang SH, et al. Insight into the regulatory mechanism of beta-arrestin2 and its emerging role in diseases. Br J Pharmacol. 2024;181:3019–38.

    Article  CAS  PubMed  Google Scholar 

  26. Wen Y, He J, Xue X, Qiu J, Xu Y, Tang Z, et al. beta-arrestin2 inhibits apoptosis and liver inflammation induced by ischemia-reperfusion in mice via AKT and TLR4 pathway. Arch Med Res. 2019;50:413–22.

    Article  CAS  PubMed  Google Scholar 

  27. Han QW, Shao QH, Wang XT, Ma KL, Chen NH, Yuan YH. CB2 receptor activation inhibits the phagocytic function of microglia through activating ERK/AKT-Nurr1 signal pathways. Acta Pharmacol Sin. 2022;43:2253–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Eng AG, Kelver DA, Hedrick TP, Swanson GT. Transduction of group I mGluR-mediated synaptic plasticity by beta-arrestin2 signalling. Nat Commun. 2016;7:13571.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mohamed R, Ahmad EA, Omran BHF, Sakr AT, Ibrahim I, Mahmoud MF, et al. Mitigation of dexamethasone-induced nephrotoxicity by modulating the activity of adrenergic receptors: Implication of Wnt/beta-arrestin2/beta-catenin pathway. Life Sci. 2022;293:120304.

    Article  CAS  PubMed  Google Scholar 

  30. Zhu J, Hu Z, Han X, Wang D, Jiang Q, Ding J, et al. Dopamine D2 receptor restricts astrocytic NLRP3 inflammasome activation via enhancing the interaction of beta-arrestin2 and NLRP3. Cell Death Differ. 2018;25:2037–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Auten RL, Davis JM. Oxygen toxicity and reactive oxygen species: the devil is in the details. Pediatr Res. 2009;66:121–7.

    Article  CAS  PubMed  Google Scholar 

  32. Mailloux RJ. Protein S-glutathionylation reactions as a global inhibitor of cell metabolism for the desensitization of hydrogen peroxide signals. Redox Biol. 2020;32:101472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sies H, Jones DP. Reactive oxygen species (ROS) are pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol. 2020;21:363–83.

    Article  CAS  PubMed  Google Scholar 

  34. Kebabian JW, Calne DB. Multiple receptors for dopamine. Nature. 1979;277:93–6.

    Article  CAS  PubMed  Google Scholar 

  35. Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, et al. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2023;51:D638–D46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Riederer P, Strobel S, Nagatsu T, Watanabe H, Chen X, Loschmann PA, et al. Levodopa treatment: impacts and mechanisms throughout Parkinson’s disease progression. J Neural Transm. 2025;132:743–79.

  37. Goedert M, Spillantini MG, Del Tredici K, Braak H. 100 years of Lewy pathology. Nat Rev Neurol. 2013;9:13–24.

    Article  CAS  PubMed  Google Scholar 

  38. Goedert M, Jakes R, Spillantini MG. The synucleinopathies: twenty years on. J Parkinson's Dis. 2017;7:S51–S69.

    Article  Google Scholar 

  39. Alam P, Bousset L, Melki R, Otzen DE. Alpha-synuclein oligomers and fibrils: a spectrum of species, a spectrum of toxicities. J Neurochem. 2019;150:522–34.

    Article  CAS  PubMed  Google Scholar 

  40. McGuire V, Van Den Eeden SK, Tanner CM, Kamel F, Umbach DM, Marder K, et al. Association of DRD2 and DRD3 polymorphisms with Parkinson’s disease in a multiethnic consortium. J Neurol Sci. 2011;307:22–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Oliveri RL, Annesi G, Zappia M, Civitelli D, De Marco EV, Pasqua AA, et al. The dopamine D2 receptor gene is a susceptibility locus for Parkinson’s disease. Mov Disord. 2000;15:127–31.

    Article  CAS  PubMed  Google Scholar 

  42. Missale C, Nash SR, Robinson SW, Jaber M, Caron MG. Dopamine receptors: from structure to function. Physiol Rev. 1998;78:189–225.

    Article  CAS  PubMed  Google Scholar 

  43. Brandebura AN, Paumier A, Onur TS, Allen NJ. Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders. Nat Rev Neurosci. 2023;24:23–39.

    Article  CAS  PubMed  Google Scholar 

  44. Yi LX, Woon HR, Saw G, Zeng L, Tan EK, Zhou ZD. Induced pluripotent stem cell-related approaches to generate dopaminergic neurons for Parkinson’s disease. Neural Regen Res. 2025;20:3193–206.

    Article  CAS  PubMed  Google Scholar 

  45. Liddelow SA, Barres BA. Reactive astrocytes: production, function, and therapeutic potential. Immunity. 2017;46:957–67.

    Article  CAS  PubMed  Google Scholar 

  46. Zhou KG, Huang YB, Zhu ZW, Jiang M, Jin LJ, Guan Q, et al. Mesencephalic astrocyte-derived neurotrophic factor inhibits neuroinflammation through autophagy-mediated alpha-synuclein degradation. Arch Gerontol Geriatr. 2025;131:105738.

    Article  CAS  PubMed  Google Scholar 

  47. Chen YJ, Xie MR, Zhou SQ, Liu F. Astrocytes-associated research in Parkinson’s disease: an explored trends analysis. Front Aging Neurosci. 2025;17:1563142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Muller HW, Junghans U, Kappler J. Astroglial neurotrophic and neurite-promoting factors. Pharm Ther. 1995;65:1–18.

    Article  CAS  Google Scholar 

  49. Liu YY, Huo D, Zeng LT, Fan GQ, Shen T, Zhang TM, et al. Mesencephalic astrocyte-derived neurotrophic factor (MANF): structure, functions and therapeutic potential. Ageing Res Rev. 2022;82:101763.

    Article  CAS  PubMed  Google Scholar 

  50. Adermark L, Lagstrom O, Loften A, Licheri V, Havenang A, Loi EA, et al. Astrocytes modulate extracellular neurotransmitter levels and excitatory neurotransmission in dorsolateral striatum via dopamine D2 receptor signaling. Neuropsychopharmacology. 2022;47:1493–502.

    Article  CAS  PubMed  Google Scholar 

  51. Xin W, Schuebel KE, Jair KW, Cimbro R, De Biase LM, Goldman D, et al. Ventral midbrain astrocytes display unique physiological features and sensitivity to dopamine D2 receptor signaling. Neuropsychopharmacology. 2019;44:344–55.

    Article  CAS  PubMed  Google Scholar 

  52. Amato S, Averna M, Farsetti E, Guidolin D, Pedrazzi M, Gatta E, et al. Control of dopamine signal in high-order receptor complex on striatal astrocytes. Int J Mol Sci. 2024;25:8610.

  53. Requie LM, Gomez-Gonzalo M, Speggiorin M, Manago F, Melone M, Congiu M, et al. Astrocytes mediate long-lasting synaptic regulation of ventral tegmental area dopamine neurons. Nat Neurosci. 2022;25:1639–50.

    Article  CAS  PubMed  Google Scholar 

  54. Shao W, Zhang SZ, Tang M, Zhang XH, Zhou Z, Yin YQ, et al. Suppression of neuroinflammation by astrocytic dopamine D2 receptors via alphaB-crystallin. Nature. 2013;494:90–4.

    Article  CAS  PubMed  Google Scholar 

  55. Bayraktar OA, Bartels T, Holmqvist S, Kleshchevnikov V, Martirosyan A, Polioudakis D, et al. Astrocyte layers in the mammalian cerebral cortex revealed by a single-cell in situ transcriptomic map. Nat Neurosci. 2020;23:500–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Floresco SB, West AR, Ash B, Moore H, Grace AA. Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission. Nat Neurosci. 2003;6:968–73.

    Article  CAS  PubMed  Google Scholar 

  57. Ben Haim L, Rowitch DH. Functional diversity of astrocytes in neural circuit regulation. Nat Rev Neurosci. 2017;18:31–41.

    Article  CAS  PubMed  Google Scholar 

  58. Corkrum M, Covelo A, Lines J, Bellocchio L, Pisansky M, Loke K, et al. Dopamine-evoked synaptic regulation in the nucleus accumbens requires astrocyte activity. Neuron. 2020;105:1036–47 e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Howe MW, Dombeck DA. Rapid signalling in distinct dopaminergic axons during locomotion and reward. Nature. 2016;535:505–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gonzalez-Rodriguez P, Zampese E, Stout KA, Guzman JN, Ilijic E, Yang B, et al. Disruption of mitochondrial complex I induces progressive Parkinsonism. Nature. 2021;599:650–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Pacelli C, Giguere N, Bourque MJ, Levesque M, Slack RS, Trudeau LE. Elevated mitochondrial bioenergetics and axonal arborization size are key contributors to the vulnerability of dopamine neurons. Curr Biol. 2015;25:2349–60.

    Article  CAS  PubMed  Google Scholar 

  62. Surmeier DJ, Obeso JA, Halliday GM. Selective neuronal vulnerability in Parkinson's disease. Nat Rev Neurosci. 2017;18:101–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Hattori N, Tanaka M, Ozawa T, Mizuno Y. Immunohistochemical studies on complexes I, II, III, and IV of mitochondria in Parkinson’s disease. Ann Neurol. 1991;30:563–71.

    Article  CAS  PubMed  Google Scholar 

  64. Parker WD Jr., Parks JK, Swerdlow RH. Complex I deficiency in the frontal cortex of Parkinson’s disease. Brain Res. 2008;1189:215–8.

    Article  CAS  PubMed  Google Scholar 

  65. Mizuno Y, Ohta S, Tanaka M, Takamiya S, Suzuki K, Sato T, et al. Deficiencies in complex I subunits of the respiratory chain in Parkinson’s disease. Biochem Biophys Res Commun. 1989;163:1450–5.

    Article  CAS  PubMed  Google Scholar 

  66. Mytilineou C, Werner P, Molinari S, Di Rocco A, Cohen G, Yahr MD. Impaired oxidative decarboxylation of pyruvate in fibroblasts from patients with Parkinson’s disease. J Neural Transm Park Dis Dement Sect. 1994;8:223–8.

    Article  CAS  PubMed  Google Scholar 

  67. Keeney PM, Xie J, Capaldi RA, Bennett JP Jr. Parkinson’s disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled. J Neurosci. 2006;26:5256–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Chang KH, Chen CM. The role of oxidative stress in Parkinson’s disease. Antioxidants. 2020;9:597.

  69. Grel H, Woznica D, Ratajczak K, Kalwarczyk E, Anchimowicz J, Switlik W, et al. Mitochondrial dynamics in neurodegenerative diseases: unraveling the role of fusion and fission processes. Int J Mol Sci. 2023;24:13033.

  70. McGregor MM, Nelson AB. Circuit mechanisms of Parkinson’s disease. Neuron. 2019;101:1042–56.

    Article  CAS  PubMed  Google Scholar 

  71. Dias V, Junn E, Mouradian MM. The role of oxidative stress in Parkinson’s disease. J Parkinsons Dis. 2013;3:461–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Mishra A, Singh S, Tiwari V, Chaturvedi S, Wahajuddin M, Shukla S. Dopamine receptor activation mitigates mitochondrial dysfunction and oxidative stress to enhance dopaminergic neurogenesis in 6-OHDA lesioned rats: a role of Wnt signalling. Neurochem Int. 2019;129:104463.

    Article  CAS  PubMed  Google Scholar 

  73. Wong YC, Kim S, Peng W, Krainc D. Regulation and function of mitochondria-lysosome membrane contact sites in cellular homeostasis. Trends Cell Biol. 2019;29:500–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Peng W, Wong YC, Krainc D. Mitochondria-lysosome contacts regulate mitochondrial Ca(2+) dynamics via lysosomal TRPML1. Proc Natl Acad Sci USA. 2020;117:19266–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Cisneros J, Belton TB, Shum GC, Molakal CG, Wong YC. Mitochondria-lysosome contact site dynamics and misregulation in neurodegenerative diseases. Trends Neurosci. 2022;45:312–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Arenas E. Wnt signaling in midbrain dopaminergic neuron development and regenerative medicine for Parkinson’s disease. J Mol Cell Biol. 2014;6:42–53.

    Article  CAS  PubMed  Google Scholar 

  77. Marchetti B, L’Episcopo F, Morale MC, Tirolo C, Testa N, Caniglia S, et al. Uncovering novel actors in astrocyte-neuron crosstalk in Parkinson’s disease: the Wnt/beta-catenin signaling cascade as the common final pathway for neuroprotection and self-repair. Eur J Neurosci. 2013;37:1550–63.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Marchetti B. Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson’s disease. Redox Biol. 2020;36:101664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. L’Episcopo F, Tirolo C, Testa N, Caniglia S, Morale MC, Serapide MF, et al. Wnt/beta-catenin signaling is required to rescue midbrain dopaminergic progenitors and promote neurorepair in ageing mouse model of Parkinson’s disease. Stem Cells. 2014;32:2147–63.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Singh S, Mishra A, Mohanbhai SJ, Tiwari V, Chaturvedi RK, Khurana S, et al. Axin-2 knockdown promotes mitochondrial biogenesis and dopaminergic neurogenesis by regulating Wnt/beta-catenin signaling in a rat model of Parkinson’s disease. Free Radic Biol Med. 2018;129:73–87.

    Article  CAS  PubMed  Google Scholar 

  81. Singh S, Mishra A, Shukla S. ALCAR exerts neuroprotective and pro-neurogenic effects by inhibition of glial activation and oxidative stress via activation of the Wnt/beta-catenin signaling in Parkinsonian rats. Mol Neurobiol. 2016;53:4286–301.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank Jiawei Zhou from Shanghai Institutes for Biological Science, Chinese Academy of Science, for providing Drd2flox/flox mice and Drd2 GFAP CKO mice. This work was supported by grants from the National Key R&D Program of China (No.2021ZD0202901), the Traditional Chinese Medicine Science and Technology Development Youth Foundation of Jiangsu Province (No. QN202407), and the National Natural Science Foundation of China (No. 82003725, No. 81991523).

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  1. These authors contributed equally: Qian-Hui Huang, Nuo-Xi Zhang.

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  1. Department of Pharmacology, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, China

    Qian-Hui Huang, Nuo-Xi Zhang, Juan-Juan Guo, Chun-Yan Fan, Yao Wei, Yang Liu & Gang Hu

  2. Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, China

    Jian-Hua Ding & Gang Hu

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Contributions

HQH and XNZ performed the majority of experimental work. JJG and CYF assisted with the experimental work. YW contributed study-specific materials and details. DJH provided the technical support. HQH wrote the manuscript. YL analyzed the data and prepared the figures. YL and GH conceived and supervised the study and revised the manuscript. YL and GH acquired the funding. All authors reviewed and gave input to improve the manuscript.

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Correspondence to Yao Wei, Yang Liu or Gang Hu.

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All animal protocols in this study were strictly following the guidelines for the use and management of experimental animals and were approved by the IACUC of Nanjing Medical University and Nanjing University of Traditional Chinese Medicine (No.1903038).

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Huang, QH., Zhang, NX., Guo, JJ. et al. Neuroprotective effect of astrocytic dopamine Drd2 receptor on mitochondrial complex I in a mouse model of Parkinson’s disease through β-arrestin2-NDUFA10 regulation. Cell Death Differ (2026). https://doi.org/10.1038/s41418-026-01756-z

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