Microglial autophagy defect causes parkinson disease-like symptoms by accelerating inflammasome activation in mice

Jinbo Cheng; Yajin Liao; Yuan Dong; Han Hu; Nannan Yang; Xiangxi Kong; Shuoshuo Li; Xiaoheng Li; Jifeng Guo; Lixia Qin; Jiezhong Yu; Cungen Ma; Jianke Li; Mingtao Li; Beisha Tang; Zengqiang Yuan

doi:10.1080/15548627.2020.1719723

Microglial autophagy defect causes parkinson disease-like symptoms by accelerating inflammasome activation in mice

Autophagy. 2020 Dec;16(12):2193-2205. doi: 10.1080/15548627.2020.1719723. Epub 2020 Jan 31.

Authors

Jinbo Cheng^{1

2}, Yajin Liao^{1

2}, Yuan Dong³, Han Hu⁴, Nannan Yang⁵, Xiangxi Kong¹, Shuoshuo Li⁶, Xiaoheng Li⁷, Jifeng Guo^{5

8}, Lixia Qin⁵, Jiezhong Yu⁹, Cungen Ma⁹, Jianke Li⁴, Mingtao Li¹⁰, Beisha Tang^{5

8}, Zengqiang Yuan^{1

11}

Affiliations

¹ The Brain Science Center, Beijing Institute of Basic Medical Sciences , Beijing, China.
² Center on Translational Neuroscience, College of Life & Environmental Science, Minzu University of China , Beijing, China.
³ Department of Biochemistry, Medical College, Qingdao University , Qingdao, Shandong, China.
⁴ Institute of Apicultural Research, Chinese Academy of Agricultural Science , Beijing, China.
⁵ Department of Neurology, Xiangya Hospital, Central South University , Changsha, Hunan, China.
⁶ The State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences , Beijing, China.
⁷ Beijing Institute for Brain Disorders, Capital Medical University , Beijing, China.
⁸ National Clinical Research Center for Geriatric Disorder, Central South University , Changsha, Hunan, China.
⁹ The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine, Research Center of Neurobiology, Shanxi University of Chinese Medicine , Taiyuan, China.
¹⁰ Department of Pharmacology and the Proteomics Center, Zhongshan School of Medicine, Sun Yat-sen University , Guangzhou, China.
¹¹ Center of Alzheimer's Disease, Beijing Institute for Brain Disorders , Beijing, China.

Abstract

Microglial activation-induced neuroinflammation is closely associated with the development of Parkinson disease (PD). Macroautophagy/autophagy regulates many biological processes, but the role of autophagy in microglial activation during PD development remains largely unclear. In this study, we showed that deletion of microglial Atg5 caused PD-like symptoms in mice, characterized by impairment in motor coordination and cognitive learning, loss of tyrosine hydroxylase (TH) neurons, enhancement of neuroinflammation and reduction in dopamine levels in the striatum. Mechanistically, we found that inhibition of autophagy led to NLRP3 (NLR family pyrin domain containing 3) inflammasome activation via PDE10A (phosphodiesterase 10A)-cyclic adenosine monophosphate (cAMP) signaling in microglia, and the sequential upregulation of downstream IL1B/IL-1β in turn increased the expression of MIF (macrophage migration inhibitory factor [glycosylation-inhibiting factor]), a pro-inflammatory cytokine. Inhibition of NLRP3 inflammasome activation by administration of MCC950, a specific inhibitor for NLRP3, decreased MIF expression and neuroinflammatory levels, and rescued the loss of TH neurons in the substantial nigra (SN). Interestingly, we found that serum MIF levels in PD patients were significantly elevated. Taken together, our results reveal an important role of autophagy in microglial activation-driven PD-like symptoms, thus providing potential targets for the clinical treatment of PD. Abbreviations: ATG: autophagy related; cAMP: cyclic adenosine monophosphate; cKO: conditional knockout; NOS2/INOS: nitric oxide synthase 2, inducible; IL1B: interleukin 1 beta; ITGAM/CD-11b: integrin alpha M/cluster of differentiation molecule 11B; MAP1LC3: microtubule-associated protein 1 light chain 3; MIF: macrophage migration inhibitory factor (glycosylation-inhibiting factor); NLRP3: NLR family pyrin domain containing 3; PBS: phosphate-buffered saline; PD: parkinson disease; PDE10A: phosphodiesterase 10A; SN: substantial nigra; TH: tyrosine hydroxylase; TNF: tumor necrosis factor; WT: wild type.

Keywords: Autophagy; cytokine; microglia; neuroinflammation; parkinson disease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy*
Autophagy-Related Protein 5 / metabolism
Brain / pathology
Cognition
Gene Deletion
Humans
Inflammasomes / metabolism*
Inflammation / pathology
Integrases / metabolism
Intramolecular Oxidoreductases / blood
Learning
Macrophage Migration-Inhibitory Factors / blood
Mice
Microglia / metabolism*
Microglia / pathology*
Motor Activity
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Neurons / metabolism
Neurons / pathology
Parkinson Disease / blood
Parkinson Disease / pathology*
Parkinson Disease / physiopathology
Phosphoric Diester Hydrolases / metabolism
Substantia Nigra / metabolism

Substances

Autophagy-Related Protein 5
Inflammasomes
Macrophage Migration-Inhibitory Factors
NLR Family, Pyrin Domain-Containing 3 Protein
Cre recombinase
Integrases
Pde10a protein, mouse
Phosphoric Diester Hydrolases
Intramolecular Oxidoreductases
MIF protein, human

Grants and funding

This work was supported by grants from the National Nature Science Foundation of China (81870839; 81630026; 81430023 and 81701187), the National Key Plan for Scientific Research and Development of China (2016YFC1306000), the National Major Project of Support Program (AWS17J013), the Beijing Nature Science Foundation (7161009) and Key Field Research and Development Program of Guangdong Province (2018B03033700).