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PARP14 inhibits microglial activation via NNT to alleviate depressive-like behaviors in mice
Xiaoyu Yu1, Tingting Yang1, Di Wu2
1Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China.
Abstract:
Microglial inflammation has been implicated in the pathophysiology of major depressive disorder; however, the underlying biological mechanisms remain inadequately understood. Consequently, we conducted a screening of the Poly ADP-ribose (PAR) polymerase (PARP) family expression in the hippocampus of chronic unpredictable stress (CUS) mouse models and investigated the specific role of PARP14 in microglial inflammation and its association with depression. Here, this study demonstrated the elevated PARP14 expression in the hippocampus of CUS mice. The knockdown of PARP14 in the hippocampus did not mitigate depressive-like behaviors in mice, whereas overexpression of PARP14 significantly mitigated these behaviors. Furthermore, PARP14 was abundant in microglia, and microglial-targeted PARP14 overexpression significantly alleviated depressive-behaviors in CUS, reduced microglial activation, and inhibited the central inflammatory responses. Mechanistically, PARP14 positively regulated nicotinamide nucleotide transhydrogenase (NNT) expression in microglia, and the inflammatory response of microglia induced by PARP14 knockdown was suppressed through NNT overexpression. Additionally, deficiency in NNT led to an accumulation of reactive oxygen species (ROS) and subsequent microglial inflammation, which was effectively inhibited by the ROS inhibitor N-Acetylcysteine. These findings suggest that PARP14 alleviates depressive-like behaviors in mice by inhibiting microglial activation via NTT-mediated clearance of ROS.
Insights
Poly (ADP-ribose) polymerase 14 (PARP14) overexpression in microglia alleviates depression-like behaviors by reducing inflammation. PARP14 inhibits microglial activation via nicotinamide nucleotide transhydrogenase-mediated reactive oxygen species clearance.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Microglial inflammation is linked to major depressive disorder (MDD) pathophysiology.
- The precise molecular mechanisms driving this link remain unclear.
- Poly (ADP-ribose) polymerase (PARP) family expression in the brain's response to stress is not fully understood.
Purpose of the Study:
- To investigate the role of PARP family expression in the hippocampus of chronic unpredictable stress (CUS) mouse models.
- To determine the specific function of PARP14 in microglial inflammation and its association with depression.
- To elucidate the molecular pathways through which PARP14 influences depressive behaviors.
Main Methods:
- Screening of PARP family gene expression in the hippocampus of CUS mice.
- In vivo manipulation of PARP14 expression (knockdown and overexpression) in mouse models.
- Assessment of depressive-like behaviors using established behavioral tests.
- Immunohistochemical analysis of microglial activation markers.
- Investigation of the interaction between PARP14, nicotinamide nucleotide transhydrogenase (NNT), and reactive oxygen species (ROS) in microglia.
Main Results:
- Elevated PARP14 expression was observed in the hippocampus of CUS mice.
- PARP14 overexpression, particularly in microglia, significantly mitigated depressive-like behaviors in CUS mice.
- Microglial-targeted PARP14 overexpression reduced microglial activation and central inflammatory responses.
- PARP14 positively regulated NNT expression in microglia, and NNT overexpression counteracted PARP14 knockdown-induced inflammation.
- NNT deficiency led to ROS accumulation and microglial inflammation, which was reversed by N-Acetylcysteine.
Conclusions:
- PARP14 plays a crucial role in alleviating depressive-like behaviors.
- PARP14 exerts its antidepressant effects by inhibiting microglial activation.
- The mechanism involves the regulation of NNT, leading to reduced ROS accumulation and suppressed neuroinflammation.
