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.

帕金森病 (PD) 是一种以中脑多巴胺能神经元进行性退化为特征的神经退行性疾病。miR-29s 家族，包括miR-29a和miR-29b1也miR-29b2和miR-29c，与衰老、新陈代谢、神经元存活和神经系统疾病有关。在本研究中，miR-29a/b1在老化和 PD 进行了调查。miR-29a/b1敲除小鼠（以下称为 29a KO）及其野生型 (WT) 对照用于分析衰老相关表型。在用神经毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 攻击后，评估了多巴胺能损伤、神经胶质激活和小鼠行为。进一步培养原代神经胶质细胞以探索潜在机制。此外，PD 患者脑脊液（CSF）中 miR-29s 的水平（n= 18) 和健康受试者 (n= 17) 被量化。与 WT 小鼠相比，29a KO 小鼠表现出显着的体重减轻、脊柱后凸，以及皮肤皱纹的增加和加深。此外，与 WT 对应物相比，29a KO 小鼠的腹部和棕色脂肪组织均减少。然而，在 MPTP 诱导的 PD 小鼠模型中，miR-29a/b1导致多巴胺能系统的损害较轻，减轻黑质纹状体通路中的神经胶质激活，随后减轻 3 个月大小鼠的运动障碍。八个月大的突变小鼠对 MPTP 中毒保持了这种抵抗力。在机械上，缺陷miR-29a/b-1促进神经营养因子在 1-Methyl-4-phenylpyridinium (MPP ⁺ ) 处理的原代混合胶质细胞和原代星形胶质细胞中的表达。在脂多糖 (LPS) 处理的原代小胶质细胞中，敲除miR-29a/b-1抑制炎症因子的表达，促进抗炎因子和神经营养因子的表达。淘汰赛miR-29a/b1增加 AMP 活化蛋白激酶 (AMPK) 的活性并抑制神经胶质细胞中的 NF-κB/p65 信号传导。此外，我们发现 PD 患者脑脊液中 miR-29a 水平升高。我们的研究结果表明，29a KO 小鼠表现出外周早衰。较少活化的神经胶质细胞的综合作用可能有助于减轻炎症反应并引发对 MPTP 中毒的抵抗力miR-29a/b1KO小鼠。