Deficiency of miR-29a/b1 leads to premature aging and dopaminergic neuroprotection in mice

Xiaochen Bai; Jinghui Wang; Xiaoshuang Zhang; Yilin Tang; Yongtao He; Jiayin Zhao; Linlin Han; Rong Fang; Zhaolin Liu; Hongtian Dong; Qing Li; Jingyu Ge; Yuanyuan Ma; Mei Yu; Ruilin Sun; Jian Wang; Jian Fei; Fang Huang

doi:10.3389/fnmol.2022.978191

Deficiency of miR-29a/b1 leads to premature aging and dopaminergic neuroprotection in mice

Front Mol Neurosci. 2022 Oct 6:15:978191. doi: 10.3389/fnmol.2022.978191. eCollection 2022.

Authors

Xiaochen Bai^{1

2

3}, Jinghui Wang¹, Xiaoshuang Zhang¹, Yilin Tang^{1

2}, Yongtao He¹, Jiayin Zhao¹, Linlin Han^{1

2}, Rong Fang¹, Zhaolin Liu¹, Hongtian Dong¹, Qing Li^{1

4}, Jingyu Ge¹, Yuanyuan Ma¹, Mei Yu¹, Ruilin Sun⁴, Jian Wang^{1

2}, Jian Fei^{4

5}, Fang Huang¹

Affiliations

¹ Department of Translational Neuroscience, MOE Frontiers Center for Brain Science, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Jing'an District Centre Hospital of Shanghai, Fudan University, Shanghai, China.
² Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
³ Department of Rehabilitation Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
⁴ Shanghai Engineering Research Center for Model Organisms, SMOC, Shanghai, China.
⁵ School of Life Science and Technology, Tongji University, Shanghai, China.

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of midbrain dopaminergic neurons. The miR-29s family, including miR-29a and miR-29b1 as well as miR-29b2 and miR-29c, are implicated in aging, metabolism, neuronal survival, and neurological disorders. In this study, the roles of miR-29a/b1 in aging and PD were investigated. miR-29a/b1 knockout mice (named as 29a KO hereafter) and their wild-type (WT) controls were used to analyze aging-related phenotypes. After challenged with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), dopaminergic injuries, glial activation, and mouse behaviors were evaluated. Primary glial cells were further cultured to explore the underlying mechanisms. Additionally, the levels of miR-29s in the cerebrospinal fluid (CSF) of PD patients (n = 18) and healthy subjects (n = 17) were quantified. 29a KO mice showed dramatic weight loss, kyphosis, and along with increased and deepened wrinkles in skins, when compared with WT mice. Moreover, both abdominal and brown adipose tissues reduced in 29a KO mice, compared to their WT counterpart. However, in MPTP-induced PD mouse model, the deficiency of miR-29a/b1 led to less severe damages of dopaminergic system and mitigated glial activation in the nigrostriatal pathway, and subsequently alleviated the motor impairments in 3-month-old mice. Eight-month-old mutant mice maintained such a resistance to MPTP intoxication. Mechanistically, the deficiency of miR-29a/b-1 promoted the expression of neurotrophic factors in 1-Methyl-4-phenylpyridinium (MPP⁺)-treated primary mixed glia and primary astrocytes. In lipopolysaccharide (LPS)-treated primary microglia, knockout of miR-29a/b-1 inhibited the expression of inflammatory factors, and promoted the expression of anti-inflammatory factors and neurotrophic factors. Knockout of miR-29a/b1 increased the activity of AMP-activated protein kinase (AMPK) and repressed NF-κB/p65 signaling in glial cells. Moreover, we found miR-29a level was increased in the CSF of patients with PD. Our results suggest that 29a KO mice display the peripheral premature senility. The combined effects of less activated glial cells might contribute to the mitigated inflammatory responses and elicit resistance to MPTP intoxication in miR-29a/b1 KO mice.

Keywords: AMPK; Parkinson’s disease; glial cells; miR-29a/b1; neuroinflammation.