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Accumulation of Prion Triggers the Enhanced Glycolysis via Activation of AMKP Pathway in Prion-Infected Rodent and Cell Models

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Abstract

Mitochondrial dysfunction is one of the hallmarks in the pathophysiology of prion disease and other neurodegenerative diseases. Various metabolic dysfunctions are identified and considered to contribute to the progression of some types of neurodegenerative diseases. In this study, we evaluated the status of glycolysis pathway in prion-infected rodent and cell models. The levels of the key enzymes, hexokinase (HK), phosphofructokinase (PFK), and pyruvate kinase (PK) were significantly increased, accompanying with markedly downregulated mitochondrial complexes. Double-stained IFAs revealed that the increased HK2 and PFK distributed widely in GFAP-, Iba1-, and NeuN-positive cells. We also identified increased levels of AMP-activated protein kinase (AMPK) and the downstream signaling. Changes of AMPK activity in prion-infected cells by the AMPK-specific inhibitor or activator induced the corresponding alterations not only in the downstream signaling, but also the expressions of three key kinases in glycolysis pathway and the mitochondrial complexes. Transient removal or complete clearance of prion propagation in the prion-infected cells partially but significantly reversed the increases of the key enzymes in glycolysis, the upregulation of AMPK signaling pathway, and the decreases of the mitochondrial complexes. Measurements of the cellular oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) showed lower OCR and higher ECAR in prion-infected cell line, which were sufficiently reversed by clearance of prion propagation. Those data indicate a metabolic reprogramming from oxidative phosphorylation to glycolysis in the brains during the progression of prion disease. Accumulation of PrPSc is critical for the switch to glycolysis, largely via activating AMPK pathway.

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Data Availability

The datasets generated during and analyzed during the current study are not publicly available due to data security but are available from the corresponding author on reasonable request.

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Funding

This work was supported by the Chinese National Natural Science Foundation Grants (81630062) and Grant (2019SKLID501, 2019SKLID603, 2019SKLID307) from the State Key Laboratory for Infectious Disease Prevention and Control, China CDC.

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Authors and Affiliations

  1. National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Disease, NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China

    Qin Fan, Kang Xiao, Ruhan A, Li-Ping Gao, Yue-Zhang Wu, Dong-Dong Chen, Chao Hu, Xiao-Xi Jia, Chu-Mou Liu, Xin Liu, Cao Chen, Qi Shi & Xiao-Ping Dong

  2. Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China

    Cao Chen & Xiao-Ping Dong

  3. China Academy of Chinese Medical Sciences, Beijing, China

    Qi Shi & Xiao-Ping Dong

  4. Shanghai Institute of Infectious Disease and Biosafety, Shanghai, China

    Xiao-Ping Dong

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  1. Qin Fan
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  2. Kang Xiao
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  3. Ruhan A
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Contributions

All authors contributed to the study conception and design. The preparations of materials and the performances of the experiments were conducted by FQ, WYZ, CDD, HC, LCM, LX, and ZWW. Data collection and analysis were conducted by FQ, XK, GLP, JXX, and CC. FQ, SQ, and DXP drafted the manuscript. SQ and XPD contributed to design, study concept, and manuscript preparation. All authors read and approved the final manuscript.

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Correspondence to Qi Shi or Xiao-Ping Dong.

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Fan, Q., Xiao, K., A, R. et al. Accumulation of Prion Triggers the Enhanced Glycolysis via Activation of AMKP Pathway in Prion-Infected Rodent and Cell Models. Mol Neurobiol (2023). https://doi.org/10.1007/s12035-023-03621-3

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