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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

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A Correction to this article was published on 15 December 2023

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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.

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Funding

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).

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Authors and Affiliations

  1. Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China

    Yan Zhou, Jialei Zhu, Yang Lv, Chenghuan Song, Jianhua Ding, Ming Xiao, Ming Lu & Gang Hu

  2. Department of Pharmacology, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, Jiangsu, 210023, China

    Gang Hu

  3. Neuroprotective Drug Discovery Key Laboratory, Department of Pharmacology, Nanjing Medical University, 101 Longmian Road, Nanjing, Jiangsu, 211166, China

    Ming Lu

  4. Department of Clinical Pharmacy, The First People’s Hospital, Shanghai Jiao Tong University, Shanghai, 200080, China

    Yan Zhou

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  1. Yan Zhou
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Correspondence to Ming Lu or Gang Hu.

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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.

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Zhou, Y., Zhu, J., Lv, Y. et al. Kir6.2 Deficiency Promotes Mesencephalic Neural Precursor Cell Differentiation via Regulating miR-133b/GDNF in a Parkinson’s Disease Mouse Model. Mol Neurobiol 55, 8550–8562 (2018). https://doi.org/10.1007/s12035-018-1005-0

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