Clk1 deficiency promotes neuroinflammation and subsequent dopaminergic cell death through regulation of microglial metabolic reprogramming

Gu, Ruinan; Zhang, Fa‐Li; Chen, Gang; Han, Chaojun; Liu, Jay; Ren, Zhaoxiang; Zhu, Yi; Waddington, John L.; Zheng, Long Tai; Zhen, Xuechu

doi:10.1016/j.bbi.2016.10.018

Cited by 45 publications

(41 citation statements)

References 51 publications

(52 reference statements)

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“…Both responses require rapid energy production which is produced when microglia undergo the metabolic switch to glycolysis . Glycolysis allows energy production and uptake of essential nutrients to support the rapid changes required by “activated” microglia in response to a stimulus, such as phagocytosis, proliferation, migration, and induction of protein synthesis for cytokine and chemokine secretion . Indeed, we identified the ability of the TREM2 variant expressing iPS‐Mg to undergo a normal switch in metabolism from a homeostatic, surveillance profile supported by oxidative phosphorylation, to one in which glycolysis is impaired.…”

Section: Discussionmentioning

confidence: 99%

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC‐derived microglia

et al. 2019

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Loss‐of‐function genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) are linked with an enhanced risk of developing dementias. Microglia, the resident immune cell of the brain, express TREM2, and microglial responses are implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely on the ability to undergo a metabolic switch to glycolysis to allow them to perform rapid plastic responses. We investigated the role of TREM2 on the microglial metabolic function in human patient iPSC‐derived microglia expressing loss of function variants in TREM2. We show that these TREM2 variant iPSC‐microglia, including the Alzheimer's disease R47H risk variant, exhibit significant metabolic deficits including a reduced mitochondrial respiratory capacity and an inability to perform a glycolytic immunometabolic switch. We determined that dysregulated PPARγ/p38MAPK signaling underlies the observed phenotypic deficits in TREM2 variants and that activation of these pathways can ameliorate the metabolic deficit in these cells and consequently rescue critical microglial cellular function such as β‐Amyloid phagocytosis. These findings have ramifications for microglial focussed‐treatments in AD.

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Section: Discussionmentioning

confidence: 99%

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC‐derived microglia

et al. 2019

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“…Recently, we have demonstrated that Clk1 was involved in metabolic reprogramming in microglia cells (Gu et al . ). Thus, we next addressed whether Clk1 alters the glycolytic metabolism in glioma cells and how the metabolic reprogramming affects its role in the chemosensitivity of GL261 glioma cells.…”

Section: Resultsmentioning

confidence: 97%

“…; Gu et al . ). This study showed that knockdown of Clk1 results in the up‐regulation of HIF‐1α and inhibition of HIF‐1α expression reversed Clk1 deficiency‐triggered aerobic glycolysis and chemoresistance of glioma cells.…”

Section: Discussionmentioning

confidence: 97%

“…Recently, we demonstrated that AMPK inactivation mediated activation of the mTOR/HIF‐1α signaling pathways participate in Clk1 deficiency‐triggered aerobic glycolysis in microglia cells (Gu et al . ). Consistently, this study also found that knockdown Clk1 in glioma cells resulted in enhanced phosphorylation of mTOR, S6K, and S6, which appeared to be mediated via inactivation of AMPK.…”

Section: Discussionmentioning

confidence: 97%

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Clk1‐regulated aerobic glycolysis is involved in glioma chemoresistance

Zhang

Yang

Zhang

et al. 2017

Journal of Neurochemistry

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Chemoresistance remains a major challenge for the treatment of glioma. In this study, we investigated the role of Clock 1 (Clk1), which encodes an enzyme that is necessary for ubiquinone biosynthesis in glioma chemoresistance in vitro. The results showed that Clk1 was highly expressed in GL261 mouse glioma cells which were most sensitive to 1,3Bis (2-chloroethyl) 1 nitrosourea (BCNU) while was low expressed in BCNU resistant cells such as glioma cancer stem cells, T98G, U87MG and U251 glioma cells. Knockdown of Clk1 in GL261 glioma cells significantly reduced BCNU- or cisplatin-induced cell apoptosis, whereas the proliferative activity and the expression of multidrug resistance-related genes including MDR1, O6-methylguanine-DNA methyltransferase, and GSTP1 were not changed. When Clk1 was re-expressed in Clk1 knockdown GL261 glioma cells, the BCNU sensitivity was restored. The mechanistic study revealed that knockdown of Clk1 in GL261 glioma cells increased aerobic glycolysis including high glucose consumption, lactate production, and up-regulation of glycolysis-associated genes. Inhibition of glycolysis can reverse the chemoresistance elicited by Clk1 knockdown in GL261 cells. Moreover, knockdown of Clk1 induced HIF-1α expression in GL261 glioma cells which was found to be mediated by AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) signaling pathway. Both metformin and rapamycin reversed the chemoresistance of Clk1 knockdown GL261 glioma cells. Over-expression of Clk1 significantly increased the sensitivity of T98G or U251 human glioblastoma cells to BCNU which was accompanied by decreased lactate secretion, decreased expression of HIF-1α, AMPK activation, and inhibition of mTOR pathway. Inhibition of glycolysis or activation of AMPK did not alter Clk1 expression in variant glioma cell lines suggesting that aerobic glycolysis is not an upstream event of Clk1 expression in glioma cells. Taken together, our results revealed, for the first time, that mitochondrial Clk1 regulated chemoresistance in glioma cells through AMPK/mTOR/HIF-1α mediated glycolysis pathway.

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“…According to the results from our previous metabolomics analysis, there was a change in glycometabolism that oxidative phosphorylation shifted to aerobic glycolysis in CdTe@ZnS QD‐activated BV2 cells, which was observed in this study by the increased glycolysis level and glycolysis ability as well as the decreased ATP production. This glycolytic shift has been reported to depend on the activation of mTOR through a dectin‐1‐Akt‐HIF‐1α pathway (Cheng et al, ; Gu et al, ). Herein, the activation of mTOR and AKT as well as mTOR and HIF‐α were observed in the hippocampus and BV2 cells treated with CdTe/ZnS QDs, respectively, and the pretreatment with mTOR inhibitor rapamycin effectively inhibited the glycolytic shift.…”

Section: Discussionmentioning

confidence: 96%

The glycolytic shift was involved in CdTe/ZnS quantum dots inducing microglial activation mediated through the mTOR signaling pathway

et al. 2019

J of Applied Toxicology

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The excellent optical property and relatively low toxicity of CdTe/ZnS core/shell quantum dots (QDs) make them an advanced fluorescent probe in the application of biomedicines, particularly in neuroscience. Thus, it is important to evaluate the biosafety of CdTe/ZnS QDs on the central nervous system (CNS). Our previous studies have suggested that the high possibility of CdTe/ZnS QDs being transported into the brain across the blood‐brain barrier resulted in microglial activation and a shift of glycometabolism, but their underlying mechanism remains unclear. In this study, when mice were injected intravenously with CdTe/ZnS QDs through tail veins, the microglial activation, polarized into both M1 phenotype and M2 phenotype, and the neuronal impairment were observed in the hippocampus. Meanwhile, the increased pro‐ and anti‐inflammatory cytokines released from BV2 microglial cells treated with CdTe/ZnS QDs also indicated that QD exposure was capable of inducing microglial activation in vitro. We further demonstrated that the glycolytic shift from oxidative phosphorylation switching into aerobic glycolysis was required in the microglial activation into M1 phenotype induced by CdTe/ZnS QD treatment, which was mediated through the mTOR signaling pathway. The findings, taken together, provide a mechanistic insight regarding the CdTe/ZnS QDs inducing microglial activation and the role of the glycolytic shift in it.

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Clk1 deficiency promotes neuroinflammation and subsequent dopaminergic cell death through regulation of microglial metabolic reprogramming

Cited by 45 publications

References 51 publications

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC‐derived microglia

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC‐derived microglia

Clk1‐regulated aerobic glycolysis is involved in glioma chemoresistance

The glycolytic shift was involved in CdTe/ZnS quantum dots inducing microglial activation mediated through the mTOR signaling pathway

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