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Kir6.2 Deficiency Promotes Mesencephalic Neural Precursor Cell Differentiation via Regulating miR-133b/GDNF in a Parkinson’s Disease Mouse Model

  • Yan Zhou
  • Jialei Zhu
  • Yang Lv
  • Chenghuan Song
  • Jianhua Ding
  • Ming Xiao
  • Ming Lu
  • Gang Hu
Article

Abstract

The loss of dopaminergic (DA) neurons in the substantia nigra (SN) is a major feature in the pathology of Parkinson’s disease (PD). Using neural stem or progenitor cells (NSC/NPCs), the prospect of replacing the missing or damaged DA neurons is very attractive for PD therapy. However, little is known about the endogenous mechanisms and molecular pathways regulating the NSC/NPC proliferation and differentiation in the development of PD. Herein, using Kir6.2 knockout (Kir6.2−/−) mice, we observed that genetic deficiency of Kir6.2 exacerbated the loss of SN DA neurons relatively early in a chronic MPTP/probenecid (MPTP/p) injection course, but rescued the damage of neurons 7 days after the last MPTP/p injection. Meanwhile, we found that Kir6.2 knockout predominantly increased the differentiation of nuclear receptor-related 1 (Nurr1+) precursors to DA neurons, indicating that Kir6.2 deficiency could activate an endogenous self-repair process. Furthermore, we demonstrated in vivo and in vitro that lack of Kir6.2 promoted neuronal differentiation via inhibiting the downregulation of glia cell line-derived neurotrophic factor (GDNF), which negatively related to the level of microRNA-133b. Notably, we revealed that Gdnf is a target gene of miR-133b and transfection of miR-133b could attenuate the enhancement of neural precursor differentiation induced by Kir6.2 deficiency. Collectively, we clarify for the first time that Kir6.2/K-ATP channel functions as a novel endogenous negative regulator of NPC differentiation, and provide a promising neuroprotective target for PD therapeutics.

Keywords

Kir6.2/K-ATP Adult neurogenesis Nurr1+ precursors Differentiation miR-133b Parkinson’s disease 

Notes

Funding Information

The work reported herein was supported by the grants from the National Natural Science Foundation of China (No. 81630099, No. 81473196, No. 81773706, No. 81573403, and No. 81603083) and the key project of Natural Science Foundation of the Higher Education Institutions of Jiangsu Province (No. 15KJA310002) and Natural Science Foundation of Jiangsu Province (BK20151559). Kir6.2 knockout mice were friendly donated by Professor Miki (Chiba University, Japan).

Compliance with Ethical Standards

All animal experiments were performed in accordance with the institutional guidelines for animal use and care, and the study protocol was approved by the ethical committee of Nanjing Medical University.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018
corrected publication April/2018

Authors and Affiliations

  1. 1.Jiangsu Key Laboratory of Neurodegeneration, Department of PharmacologyNanjing Medical UniversityNanjingChina
  2. 2.Department of PharmacologyNanjing University of Chinese MedicineNanjingChina
  3. 3.Neuroprotective Drug Discovery Key Laboratory, Department of PharmacologyNanjing Medical UniversityNanjingChina
  4. 4.Department of Clinical Pharmacy, The First People’s HospitalShanghai Jiao Tong UniversityShanghaiChina

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