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HACE1 negatively regulates neuroinflammation through ubiquitylating and degrading Rac1 in Parkinson’s disease models


Neuroinflammation plays an important role in neurodegenerative diseases, such as Parkinson’s disease (PD) and Alzheimer’s disease. HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1) is a tumor suppressor. Recent evidence suggests that HACE1 may be involved in oxidative stress responses. Due to the critical role of ROS in neuroinflammation, we speculated that HACE1 might participate in neuroinflammation and related neurodegenerative diseases, such as PD. In this study, we investigated the role of HACE1 in neuroinflammation of PD models. We showed that HACE1 knockdown exacerbated LPS-induced neuroinflammation in BV2 microglial cells in vitro through suppressing ubiquitination and degradation of activated Rac1, an NADPH oxidase subunit. Furthermore, we showed that HACE1 exerted vital neuronal protection through increasing Rac1 activity and stability in LPS-treated SH-SY5Y cells, as HACE1 knockdown leading to lower tolerance to LPS challenge. In MPTP-induced acute PD mouse model, HACE1 knockdown exacerbated motor deficits by activating Rac1. Finally, mutant α-synuclein (A53T)-overexpressing mice, a chronic PD mouse model, exhibited age-dependent reduction of HACE1 levels in the midbrain and striatum, implicating that HACE1 participated in PD pathological progression. This study for the first time demonstrates that HACE1 is a negative regulator of neuroinflammation and involved in the PD pathogenesis by regulating Rac1 activity. The data support HACE1 as a potential target for PD and other neurodegenerative diseases.

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Fig. 1: HACE1 knockdown in BV2 cells exacerbated neuroinflammation.
Fig. 2: HACE1 regulated neuroinflammation through the Rac1-NADPH oxidase pathway.
Fig. 3: HACE1 promoted the ubiquitination and degradation of Rac1- GTP.
Fig. 4: HACE1 protected SH‐SY5Y cells from LPS‐mediated neurotoxicity.
Fig. 5: HACE1 knockdown exacerbated behavior impairments in the MPTP-induced mouse model.
Fig. 6: HACE1 is reduced in the brain of A53T transgenic mice.
Fig. 7: Schematic diagram of HACE1 role in regulating the neuroinflammatory responses of BV2 microglial cells.


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The study was supported by grants from Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (No. 2016-I2M-3-011), Chinese Academy of Medical Sciences Fundamental Research Funds for the Central Universities (No. 2018RC350002), National Natural Science Foundation of China (No. 81630097, 81773718, 21772235).

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Authors and Affiliations



CXZ and DZ designed the study and drafted the manuscript. CXZ, LW, HYY, JMS carried out behavioral tests, immunohistochemistry and Western blot assay. HL, ZHZ, CJ, FYY and FYL participated in the Western blot assay. XQB revised the manuscript.

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Correspondence to Dan Zhang.

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The authors declare no competing interests.

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Zang, Cx., Wang, L., Yang, Hy. et al. HACE1 negatively regulates neuroinflammation through ubiquitylating and degrading Rac1 in Parkinson’s disease models. Acta Pharmacol Sin 43, 285–294 (2022).

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  • HACE1
  • Rac1 activity
  • neuroinflammation
  • LPS
  • BV2 microglial cells
  • MPTP-induced acute PD mouse model
  • α-synuclein transgenic mice
  • Parkinson’s disease

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